Furopyrimidinedione derivatives as trpai modulators

ABSTRACT

The present invention is related to novel furopyrimidinedione derivatives as TRPA (Transient Receptor Potential subfamily A) modulators. In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by TRPA1 (Transient Receptor Potential subfamily A, member 1). Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders modulated by TRPA1.

RELATED APPLICATIONS

This application claims the benefit of Indian Patent Application Nos665/MUM/2009 filed on Mar. 23, 2009; 2213/MUM/2009 filed on Sep. 23,2009; 2906/MUM/2009 filed on Dec. 16, 2009 and U.S. ProvisionalApplication Nos 61/171,355 filed on Apr. 21, 2009; 61/251,994; filed onOct. 15, 2009 and 61/294,470 filed on Jan. 12, 2010 all of which arehereby incorporated by reference.

TECHNICAL FIELD

The present patent application relates to furopyrimidinedionederivatives as TRPA1 modulators with transient receptor potentialankyrin1 (TRPA1) activity.

BACKGROUND OF THE INVENTION

The transient receptor potential (TRP) channels or receptors are painreceptors. They have been classified into seven subfamilies: TRPC(canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin),TRPML (mucolipin), TRPA (ankyrin, ANKTM1) and TRPN (NOMPC) families. TheTRPC family can be divided into 4 subfamilies (i) TRPC 1 (ii) TRPC2(iii) TRPC3, TRPC6, TRPC7 and (iv) TRPC4, TRPC5 based on sequencefunctional similarities. Currently the TRPV family has 6 members. TRPV5and TRPV6 are more closely related to each other than to TRPV1, TRPV2,TRPV3 or TRPV4. TRPA1 is most closely related to TRPV3 and is moreclosely related to TRPV1 and TRPV2 than to TRPV5 and TRPV6. The TRPMfamily has 8 members. Constituents include the following: the foundingmember TRPM1 (melastatin or LTRPC1), TRPM3 (KIAA1616 or LTRPC3), TRPM7(TRP-PLIK, ChaK(1), LTRPC7), TRPM6 (ChaK2), TRPM2 (TRPC7 or LTRPC2),TRPM8 (TRP-p8 or CMR1), TRPM5 (MTR1 or LTRPC5) and TRPM4 (F1120041 orLTRPC4). The TRPML family consists of the mucolipins, which includeTRPML1 (mucolipin 1), TRPML2 (mucolipin 2) and TRPML3 (mucolipin 3). TheTRPP family consists of two groups of channels: those predicted to havesix transmembrane domains and those that have eleven. TRPP2 (PKD2),TRPP3 (PKD2L1), TRPP5 (PKD2L2) are all predicted to have sixtransmembrane domains. TRPP1 (PKD1, PC1), PKD-REJ and PKD-1L1 are allthought to have eleven transmembrane domains. The sole mammalian memberof the TRPA family is ANKTM1.

It is believed TRPA1 is expressed in nociceptive neurons. Nociceptiveneurons of the nervous system sense the peripheral damage and transmitpain signals. TRPA1 is membrane bound and most likely acts as aheterodimeric voltage gated channel. It is believed to have a particularsecondary structure, its N-terminus is lined with a large number ofankyrin repeats which are believed to form a spring-like edifice. TRPA1is activated by a variety of noxious stimuli, including coldtemperatures (activated at 17° C.), pungent natural compounds (e.g.,mustard, cinnamon and garlic) and environmental irritants (MacPherson,L. J. et al., Nature, 2007, 445; 541-545). Noxious compounds activateTRPA1 ion channels through covalent modification of cysteines to formcovalently linked adducts. Variety of endogenous molecules producedduring tissue inflammation/injury have been identified as pathologicalactivators of TRPA1 receptor. These include hydrogen peroxide which isproduced due to oxidative stress generated during inflammation, alkenylaldehyde 4-HNE—an intracellular lipid peroxidation product andcyclopentenone prostaglandin 15dPGJ2 which is produced from PGD2 duringinflammation/allergic response. TRPA1 is also activated in receptordependant fashion by Bradykinin (BK) which is released during tissueinjury at peripheral terminals

The difference between TRPA1 and other TRP receptors is that TRPA1ligand binding persists for hours due to which the physiologicalresponse (e.g., pain) is greatly prolonged. Hence to dissociate theelectrophile, an effective antagonist is required.

WO 2009/158719, WO 2009/002933, WO 2008/0949099, WO 2007/073505, WO2004/055054 and WO 2005/089206 describe the TRP channels as the targetsfor the treatment of pain and related conditions.

In efforts to discover better analgesics for the treatment of both acuteand chronic pain and to develop treatments for various neuropathic andnociceptive pain states, there exists a need for a more effective andsafe therapeutic treatment of diseases, conditions and/or disordersmodulated by TRPA1.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula (I):

or a pharmaceutically acceptable salt thereof,

wherein,

R¹ and R², which may be the same or different, are independentlyselected from hydrogen, substituted or unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl,(CR^(x)R^(Y))_(n)OR^(x), COR^(x), COOR^(x), CONR^(x)R^(y),(CH₂)_(n)NR^(x)R^(y), (CH₂)_(n)CHR^(x)R^(y), (CH₂)_(n)NR^(x)R^(y) and(CH₂)_(n)NHCOR^(x);

R³ is selected from hydrogen, substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl and cycloalkenyl;

Z₁ and Z₂ are independently oxygen or CR^(a); with a proviso that one ofZ₁ or Z₂ is always oxygen and other is CR^(a);

L is a linker selected from —(CR^(x)R^(y))_(n)—, —O—(CR^(x)R^(y))_(n)—,—C(O)—, —NR^(x)—, —S(O)_(m)NR^(x)—, —NR^(x)(CR^(x)R^(y))_(n)— and—S(O)_(m)NR^(x)(CR^(x)R^(y))_(n);

R^(a) is selected from hydrogen, cyano, substituted or unsubstitutedalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring,heterocyclylalkyl, OR^(x), (CR^(x)R^(y))_(n)OR^(x), COR^(x), COOR^(x),CONR^(x)R^(y), S(O)_(m)NR^(x)R^(y), NR^(x)R^(y),NR^(x)(CR^(x)R^(y))_(n)OR^(x), (CH₂)_(n)NR^(x)R^(Y),(CH₂)_(n)CHR^(x)R^(y), NR^(x)(CR^(x)R^(Y))_(n)CONR^(x)R^(Y),(CH₂)_(n)NHCOR^(x), (CH₂)_(n)NH(CH₂)_(n)SO₂R^(x), (CH₂)_(n)NHSO₂R^(x),SR^(x) and OR^(x);

U is selected from —(CR^(x)R^(y))_(n)—, substituted or unsubstitutedaryl, substituted or unsubstituted five membered heterocycles selectedfrom the group consisting of thiazole, isothiazole, oxazole, isoxazole,thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene,pyrroles, 1,2,3-triazoles and 1,2,4-triazole, or substituted orunsubstituted six membered heterocycle selected from the groupconsisting of pyrimidine, pyridine and pyridazine;

V is selected from hydrogen, cyano, nitro, —NR^(x)R^(y), halogen,hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy,cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl,heterocyclic ring and heterocyclylalkyl, —C(O)OR^(x), —OR^(x),

—C(O)NR^(x)R^(y), —C(O)R^(x) and —SO₂NR^(x)R^(y); or

alternatively, U and V together may form an optionally substituted 3 to7 membered saturated or unsaturated cyclic ring that may optionallyinclude one or more heteroatoms selected from O, S and N;

at each occurrence, R^(x) and R^(y) are independently selected fromhydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring andheterocyclylalkyl; and

at each occurrence, ‘m’ and ‘n’ are independently selected from 0 to 2,both inclusive.

According to one embodiment, there is provided a compound of the formula(Ia):

or a pharmaceutically acceptable salt thereof,

wherein,

R¹ and R², which may be the same or different, are independentlyselected from hydrogen, substituted or unsubstituted alkyl, haloalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl,(CR^(x)R^(y))_(n)OR^(x), COR^(x), COOR^(x), CONR^(x)R^(y),(CH₂)_(n)NR^(x)R^(y), (CH₂)_(n)CHR^(x)R^(y), (CH₂)_(n)NR^(x)R^(y) and(CH₂)_(n)NHCOR^(x);

R^(a) is selected from hydrogen, cyano, substituted or unsubstitutedalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring,heterocyclylalkyl, OR^(x), (CR^(x)R^(y))_(n)OR^(x), COR^(x), COOR^(x),CONR^(x)R^(y), S(O)_(m)NR^(x)R^(y), NR^(x)R^(y),NR^(x)(CR^(x)R^(y))_(n)OR^(x), (CH₂)_(n)NR^(x)R^(y),(CH₂)_(n)CHR^(x)R^(y), NR^(x)(CR^(x)R^(y))_(n)CONR^(x)R^(y),(CH₂)_(n)NHCOR^(x), (CH₂)_(n)NH(CH₂)_(n)SO₂R^(x), (CH₂)_(n)NHSO₂R^(x),SR^(x) and OR^(x);

U is selected from —(CR^(x)R^(y))_(n)—, substituted or unsubstitutedaryl, substituted or unsubstituted five membered heterocycles selectedfrom the group consisting of thiazole, isothiazole, oxazole, isoxazole,thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene,pyrroles, 1,2,3-triazoles and 1,2,4-triazole, or substituted orunsubstituted six membered heterocycle selected from the groupconsisting of pyrimidine, pyridine and pyridazine;

V is selected from hydrogen, cyano, nitro, —NR^(x)R^(y), halogen,hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy,cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl,heterocyclic ring and heterocyclylalkyl, —C(O)OR^(x), —OR^(x),

—C(O)NR^(x)R^(y), —C(O)R^(x) and —SO₂NR^(x)R^(y); or

alternatively, U and V together may form an optionally substituted 3 to7 membered saturated or unsaturated cyclic ring that may optionallyinclude one or more heteroatoms selected from O, S and N;

at each occurrence, R^(x) and R^(y) are independently selected fromhydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring andheterocyclylalkyl; and

at each occurrence, ‘m’ and ‘n’ are independently selected from 0 to 2,both inclusive.

The embodiments below are illustrative of the present invention and arenot intended to limit the claims to the specific embodimentsexemplified.

According to one embodiment, specifically provided are compounds of theformula (Ia) in which R^(a) is hydrogen or (C₁-C₄) alkyl.

According to yet another embodiment, specifically provided are compoundsof the formula (Ia) in which R¹ and R² are methyl.

According to yet another embodiment, specifically provided are compoundsof the formula (Ia) in which ‘U’ is substituted or unsubstituted fivemembered heterocycle, preferably thiazole, imidazole, isoxazole,pyrazole or thiadiazole and the substituent is alkyl, halogen,haloalkyl, hydroxyalkyl or substituted or unsubstituted phenyl.

According to yet another embodiment, specifically provided are compoundsof the formula (Ia) in which ‘U’ is substituted or unsubstituted sixmembered heterocycle, preferably pyridine.

According to yet another embodiment, specifically provided are compoundsof the formula (Ia) in which ‘U’ is substituted or unsubstituted aryl,preferably phenyl.

According to yet another embodiment, specifically provided are compoundsof the formula (Ia) in which ‘U’ is —CH₂—CH₂-linker.

According to yet another embodiment, specifically provided are compoundsof the formula (Ia) in which ‘U’ and ‘V’ are fused to form benzothiazolering which is optionally substituted with one or more halogens.

According to yet another embodiment, specifically provided are compoundsof the formula (Ia) in which ‘V’ is substituted or unsubstituted aryl,preferably phenyl. In this embodiment the substituents on phenyl may beone or more and are independently selected from halogen (for example F,Cl or Br), cyano, alkyl (for example iso-butyl or tert-butyl), haloalkyl(for example CF₃), alkoxy (for example OCH₃, OCH₂CH(CH₃)₂, OCH₂C(CH₃)₃or OCH₂CH₂CH(CH₃)₂), haloalkoxy (for example OCHF₂, OCF₃, OCH₂CF₃, orOCH₂CH₂CF₃) and cycloalkylalkoxy (for example cyclopropylmethoxy).

According to one embodiment, there is provided a compound of the formula(Ib):

or a pharmaceutically acceptable salt thereof,

wherein,

U, V, R¹, R² and R^(a) are as defined above.

The embodiments below are illustrative of the present invention and arenot intended to limit the claims to the specific embodimentsexemplified.

According to one embodiment, specifically provided are compounds of theformula (Ib) in which R^(a) is hydrogen or (C₁-C₄) alkyl.

According to another embodiment, specifically provided are compounds ofthe formula (Ib) in which R¹ and R² are methyl.

According to yet another embodiment, specifically provided are compoundsof the formula (Ib) in which ‘U’ is substituted or unsubstituted fivemembered heterocycle, preferably thiazole.

According to yet another embodiment, specifically provided are compoundsof the formula (Ib) in which ‘V’ is substituted or unsubstituted aryl,preferably phenyl. In this embodiment the substituents on phenyl may beone or more and are independently selected from halogen (for example F,Cl or Br), alkyl (CH₂CH(CH₃)₂), haloalkyl (for example CF₃) andhaloalkoxy (for example OCHF₂, OCF₃ or OCH₂CF₃).

According to one embodiment, there is provided a compound of the formula(Ic):

or a pharmaceutically acceptable salt thereof,

wherein,

R¹, R² and R^(a) which may be the same or different, are eachindependently hydrogen or (C₁-C₄)alkyl; and

R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹, which may be same or different, are eachindependently selected from the group comprising of hydrogen, halogen,cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl,alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl,heteroarylalkyl, heterocyclic ring and heterocyclylalkyl.

The embodiments below are illustrative of the present invention and arenot intended to limit the claims to the specific embodimentsexemplified.

According to one embodiment, specifically provided are compounds of theformula (Ic) in which R^(a) is hydrogen or (C₁-C₄) alkyl, for examplemethyl.

According to another embodiment, specifically provided are compounds ofthe formula (Ic) in which R¹ and R² are methyl.

According to another embodiment, specifically provided are compounds ofthe formula (Ic) in which R⁴, R⁵, R⁶ and R⁷ are independently selectedfrom hydrogen, fluoro, chloro, bromo, iso-butyl, 2,2-dimethylpropoxy,iso-butoxy, 3-methylbutoxy, difluoromethxy, trifluoromethyltrifluoromethoxy, trifluoroethoxy, trifluoropropoxy, andcyclopropylmetoxy.

According yet another embodiment, specifically provided are compounds ofthe formula (Ic) in which R⁸ is hydrogen.

According to one embodiment, specifically provided are compounds of theformula (Ic) in which R⁹ is hydrogen or (C₁-C₄) alkyl.

Particularly contemplated are compounds of the formulas (I), (Ia), (Ib)and (Ic), which possess IC₅₀ of less than 250 nM, preferably, less than100 nM, more preferably, less than 50 nM with respect to TRPA1 activityas measured by method as described in the present patent application.

It should be understood that the formulas (I), (Ia), (Ib) and (Ic)structurally encompasses all stereoisomers, enantiomers anddiastereomers, and pharmaceutically acceptable salts that may becontemplated from the chemical structure of the genera described herein.

The compound of the present invention as TRPA1 modulator is used hereinbecause it is more selective for one TRP isoform than others, e.g.,2-fold, 5-fold, 10-fold, and more preferably at least 20, 40, 50, 60,70, 80, or at least 100- or even 1000-fold more selective for TRPA1 overone or more of TRPC6, TRPV5, TRPV6, TRPM8, TRPV1, TRPV2, TRPV4 and/orTRPV3.

In accordance with another aspect, the present patent applicationprovides a pharmaceutical composition that includes at least onecompound described herein and at least one pharmaceutically acceptableexcipient (such as a pharmaceutically acceptable carrier or diluent).Preferably, the pharmaceutical composition comprises a therapeuticallyeffective amount of at least one compound described herein. Thecompounds described in the present patent application may be associatedwith a pharmaceutically acceptable excipient (such as a carrier or adiluent) or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container.

The compounds of the present invention can be administered aspharmaceutical composition containing, for example, 0.1 to 99.5% (morepreferably, 0.5 to 90%) of active ingredient in combination with apharmaceutically acceptable carrier. The ultimate dose will depend onthe condition being treated, the route of administration and the age,weight and condition of the patient and will be the doctor's discretion.

Compounds of the present invention may be used in the manufacture ofmedicaments for the treatment of any diseases disclosed herein. Thecompounds and pharmaceutical compositions described herein are usefulfor modulating TRPA1 receptors, wherein modulation is believed to berelated to a variety of disease states.

The compound of the present invention can be administered alone or incombination with other therapeutic agents. For instance, the TRPA1modulator is administered conjointly with one or more of ananti-inflammatory agent, anti-acne agent, anti-wrinkle agent,anti-scarring agent, anti-psoriatic agent, anti-proliferative agent,anti-fungal agent, anti-viral agent, anti-septic agent, anti-migraineagent, keratolytic agent, or a hair growth inhibitor

In accordance with another aspect, the present patent applicationfurther provides a method of inhibiting TRPA1 receptors in a subject inneed thereof by administering to the subject one or more compoundsdescribed herein in the amount effective to cause inhibition of suchreceptor.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The terms “halogen” or “halo” includes fluorine, chlorine, bromine oriodine.

The term “alkyl” refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to eight carbon atoms, and which isattached to the rest of the molecule by a single bond, e.g., methyl,ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and1,1-dimethylethyl (tert-butyl). The term “C₁₋₆ alkyl” refers to an alkylchain having 1 to 6 carbon atoms. Unless set forth or recited to thecontrary, all alkyl groups described herein may be straight chain orbranched, substituted or unsubstituted

The term “alkenyl” refers to an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be a straight or branched chainhaving 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl(allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.Unless set forth or recited to the contrary, all alkenyl groupsdescribed herein may be straight chain or branched, substituted orunsubstituted.

The term “alkynyl” refers to a straight or branched chain hydrocarbylradical having at least one carbon-carbon triple bond and having 2 toabout 12 carbon atoms (with radicals having 2 to about 10 carbon atomsbeing preferred) e.g., ethynyl, propynyl and butynyl. Unless set forthor recited to the contrary, all alkynyl groups described herein may bestraight chain or branched, substituted or unsubstituted.

The term “alkoxy” refers to a straight or branched, saturated aliphatichydrocarbon radical bonded to an oxygen atom that is attached to a corestructure. Examples of alkoxy groups include but are not limited tomethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy,pentoxy, 3-methyl butoxy and the like. Unless set forth or recited tothe contrary, all alkoxy groups described herein may be straight chainor branched, substituted or unsubstituted.

The term “haloalkyl” and “haloalkoxy” means alkyl or alkoxy, as the casemay be, substituted with one or more halogen atoms, where alkyl andalkoxy groups are as defined above. The term “halo” is used hereininterchangeably with the term “halogen” means F, Cl, Br or I. Examplesof “haloalkyl” include but are not limited to trifluoromethyl,difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl4,4,4-trifluorobutyl, 4,4-difluorocyclohexyl, chloromethyl,dichloromethyl, trichloromethyl, 1-bromoethyl and the like. Examples of“haloalkoxy” include but are not limited to fluoromethoxy,difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy,trichloromethoxy, 1-bromoethoxy and the like. Unless set forth orrecited to the contrary, all “haloalkyl” and “haloalkoxy” groupsdescribed herein may be straight chain or branched, substituted orunsubstituted.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. Examples of multicyclic cycloalkyl groupsinclude, but are not limited to, perhydronapththyl, adamantyl andnorbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g.,spiro(4,4) non-2-yl. Unless set forth or recited to the contrary, allcycloalkyl groups described herein may be substituted or unsubstituted.

The term “cycloalkylalkyl” refers to a cyclic ring-containing radicalhaving 3 to about 8 carbon atoms directly attached to an alkyl group.The cycloalkylalkyl group may be attached to the main structure at anycarbon atom in the alkyl group that results in the creation of a stablestructure. Non-limiting examples of such groups includecyclopropylmethyl, cyclobutylethyl and cyclopentylethyl. Unless setforth or recited to the contrary, all cycloalkylalkyl groups describedherein may be substituted or unsubstituted.

The term “cycloalkylalkoxy” is used to denote alkoxy substituted withcycloalkyl, wherein ‘alkoxy’ and ‘cycloalkyl’ are as defined above(either in the broadest aspect or a preferred aspect). Examples ofcycloalkylalkoxy groups include cyclopropylmethoxy, 1- or2-cyclopropylethoxy, 1-, 2- or 3-cyclopropylpropoxy, 1-, 2-, 3- or4-cyclopropyl-butoxy, cyclobutylmethoxy, 1- or 2-cyclobutylethoxy, 1-,2- or 3-cyclobutylpropoxy, 1-, 2-, 3- or 4-cyclobutylbutoxy,cyclopentylmethoxy, 1- or 2-cyclopentylethoxy, 1-, 2- or3-cyclopentylpropoxy, 1-, 2-, 3- or 4-cyclopentylbutoxy,cyclohexylmethoxy, 1- or 2-cyclohexylethoxy and 1-, 2- or3-cyclohexylpropoxy. Preferably, ‘cycloalkylalkoxy’ is(C₃₋₆)cycloalkyl-(C₁₋₆)alkoxy. Unless set forth or recited to thecontrary, all cycloalkylalkoxy groups described herein may besubstituted or unsubstituted.

The term “cycloalkenyl” refers to a cyclic ring-containing radicalhaving 3 to about 8 carbon atoms with at least one carbon-carbon doublebond, such as cyclopropenyl, cyclobutenyl and cyclopentenyl. Unless setforth or recited to the contrary, all cycloalkenyl groups describedherein may be substituted or unsubstituted.

The term “aryl” means a carbocyclic aromatic system containing one, twoor three rings wherein such rings may be fused. If the rings are fused,one of the rings must be fully unsaturated and the fused ring(s) may befully saturated, partially unsaturated or fully unsaturated. The term“fused” means that a second ring is present (ie, attached or formed) byhaving two adjacent atoms in common (i.e., shared) with the first ring.The term “fused” is equivalent to the term “condensed”. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl. Unless set forth or recited to the contrary, allaryl groups described herein may be substituted or unsubstituted.

The term “arylalkyl” refers to an aryl group as defined above directlybonded to an alkyl group as defined above, e.g., —CH₂C₆H₅ or —C₂H₄C₆H₅.Unless set forth or recited to the contrary, all arylalkyl groupsdescribed herein may be substituted or unsubstituted.

The term “heterocyclic ring” refers to a stable 3- to 15-membered ringradical which consists of carbon atoms and from one to five heteroatomsselected from nitrogen, phosphorus, oxygen and sulfur. For purposes ofthis invention, the heterocyclic ring radical may be a monocyclic,bicyclic or tricyclic ring system, which may include fused, bridged orspiro ring systems and the nitrogen, phosphorus, carbon, oxygen orsulfur atoms in the heterocyclic ring radical may be optionally oxidizedto various oxidation states. In addition, the nitrogen atom may beoptionally quaternized; and the ring radical may be partially or fullysaturated (i.e., heterocyclic or heteroaryl). Examples of suchheterocyclic ring radicals include, but are not limited to, azetidinyl,acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl,cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl,pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl,isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoqinolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl,pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl,morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl,isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl,isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl,benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl,oxadiazolyl, chromanyl and isochromanyl. The heterocyclic ring radicalmay be attached to the main structure at any heteroatom or carbon atomthat results in the creation of a stable structure. Unless set forth orrecited to the contrary, all heterocyclic ring described herein may besubstituted or unsubstituted.

The term “heterocyclyl” refers to a heterocyclic ring radical as definedabove. The heterocyclyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure. Unless set forth or recited to the contrary, allheterocyclyl groups described herein may be substituted orunsubstituted.

The term “heterocyclylalkyl” refers to a heterocyclic ring radicaldirectly bonded to an alkyl group. The heterocyclylalkyl radical may beattached to the main structure at any carbon atom in the alkyl groupthat results in the creation of a stable structure. Unless set forth orrecited to the contrary, all heterocyclylalkyl groups described hereinmay be substituted or unsubstituted.

The term “heteroaryl” refers to an aromatic heterocyclic ring radical.The heteroaryl ring radical may be attached to the main structure at anyheteroatom or carbon atom that results in the creation of a stablestructure. Unless set forth or recited to the contrary, all heteroarylgroups described herein may be substituted or unsubstituted.

The term “heteroarylalkyl” refers to a heteroaryl ring radical directlybonded to an alkyl group. The heteroarylalkyl radical may be attached tothe main structure at any carbon atom in the alkyl group that results inthe creation of a stable structure. Unless set forth or recited to thecontrary, all heteroarylalkyl groups described herein may be substitutedor unsubstituted.

Unless otherwise specified, the term “substituted” as used herein refersto substitution with any one or more or any combination of the followingsubstituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio(═S), substituted or unsubstituted alkyl, substituted or unsubstitutedhaloalkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted haloalkoxy, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substitutedor unsubstituted cycloalkenyl, substituted or unsubstituted amino,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocyclylalkyl ring,substituted or unsubstituted heteroarylalkyl, substituted orunsubstituted heterocyclic ring, substituted or unsubstituted guanidine,—COOR^(x′), —C(O)R^(x′), —C(S)R^(x′), —C(O)NR^(x′)R^(3′),—C(O)ONR^(x′)R^(y′), —NR^(x′)CONR^(y′)R^(z′), —N(R^(x′))SOR^(y′),—N(R^(x′))SO₂R^(y′), —(═N—N(R^(x′))R^(y′)), —NR^(x′)C(O)OR^(3′),—NR^(x′)R^(y′), —NR^(x′)C(O)R^(3′), —NR^(x′)C(S)R^(y′),—NR^(x′)C(S)NR^(y′)R^(z′), —SONR^(x′)R^(y′), —SO₂NR^(x′)R^(y′),—OR^(x′), —OR^(x′)C(O)NR^(y′)R^(z′), —OR^(x′)C(O)OR^(y′), —OC(O)R^(x′),—OC(O)NR^(x′)R^(y′), —R^(x′)NR^(y′)C(O)R^(z′), —R^(x′)OR^(y′),—R^(x′)C(O)OR^(y′), —R^(x′)C(O)NR^(y′)R^(z′), —R^(x′)C(O)R^(y′),—R^(x′)OC(O)R^(y′), —SR^(x′), —SOR^(x′), —SO₂R^(x′) and —ONO₂, whereinR^(x′), R^(y′) and R^(z′) are independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted amino,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted heterocyclylalkyl ring, substituted orunsubstituted heteroarylalkyl or substituted or unsubstitutedheterocyclic ring.

The term “treating” or “treatment” of a state, disorder or conditionincludes; (a) preventing or delaying the appearance of clinical symptomsof the state, disorder or condition developing in a subject that may beafflicted with or predisposed to the state, disorder or condition butdoes not yet experience or display clinical or subclinical symptoms ofthe state, disorder or condition; (b) inhibiting the state, disorder orcondition, i.e., arresting or reducing the development of the disease orat least one clinical or subclinical symptom thereof; or (c) relievingthe disease, i.e., causing regression of the state, disorder orcondition or at least one of its clinical or subclinical symptoms.

The term “subject” includes mammals (especially humans) and otheranimals, such as domestic animals (e.g., household pets including catsand dogs) and non-domestic animals (such as wildlife).

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a subject for treating a state, disorder orcondition, is sufficient to effect such treatment. The “therapeuticallyeffective amount” will vary depending on the compound, the disease andits severity and the age, weight, physical condition and responsivenessof the subject to be treated.

The compounds described in the present patent application may formsalts. Non-limiting examples of pharmaceutically acceptable saltsforming part of this patent application include salts derived frominorganic bases salts of organic bases, salts of chiral bases, salts ofnatural amino acids and salts of non-natural amino acids.

Certain compounds of the present invention, including compounds offormula (I), (Ia), (Ib) and (Ic) are capable of existing instereoisomeric forms (e.g. diastereomers and enantiomers). The presentinvention includes these stereoisomeric forms (including diastereomersand enantiomers) and mixtures of them. The various stereoisomeric formsof the compounds of the present invention may be separated from oneanother by methods known in the art or a given isomer may be obtained bystereospecific or asymmetric synthesis. Tautomeric forms and mixtures ofcompounds described herein are also contemplated.

Pharmaceutical Compositions

The pharmaceutical composition of the present patent applicationincludes at least one compound described herein and at least onepharmaceutically acceptable excipient (such as a pharmaceuticallyacceptable carrier or diluent). Preferably, the pharmaceuticalcomposition includes the compound(s) described herein in an amountsufficient to inhibit TRPA1 in a subject (e.g., a human). The inhibitoryactivity of compounds falling within the formulas (I), (Ia), (Ib) and(Ic) may be measured by an assay provided below.

The compound of the present invention may be associated with apharmaceutically acceptable excipient (such as a carrier or a diluent)or be diluted by a carrier, or enclosed within a carrier which can be inthe form of a capsule, sachet, paper or other container.

The pharmaceutical compositions may be prepared by techniques known inthe art. For example, the active compound can be mixed with a carrier,or diluted by a carrier, or enclosed within a carrier, which may be inthe form of an ampoule, capsule, sachet, paper, or other container. Whenthe carrier serves as a diluent, it may be a solid, semi-solid, orliquid material that acts as a vehicle, excipient, or medium for theactive compound. The active compound can be adsorbed on a granular solidcontainer, for example, in a sachet.

The pharmaceutical compositions may be in conventional forms, forexample, capsules, tablets, aerosols, solutions, suspensions or productsfor topical application.

Methods of Treatment

The compounds and pharmaceutical compositions of the present inventioncan be administered to treat any disorder, condition, or diseasetreatable by inhibition of TRPA1. For instance, the compounds andpharmaceutical compositions of the present invention are suitable fortreatment or prophylaxis of the following diseases, conditions anddisorders mediated or associated with the activity of TRPA1 receptors:pain, chronic pain, complex regional pain syndrome, neuropathic pain,postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, backpain, visceral pain, cancer pain, algesia, neuralgia, migraine,neuropathies, chemotherapy-induced neuropathies, eye-irritation,bronchial-irritation, skin-irritation (atopic dermatitis), Frost-bites(cold-bite), spasticity, catatonia, catalepsy, parkinsons, diabeticneuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia,fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke, poststroke pain, multiple sclerosis, respiratory diseases, asthma, cough,COPD, inflammatory disorders, oesophagitis, gastroeosophagal refluxdisorder (GERD), irritable bowel syndrome, inflammatory bowel disease,pelvic hypersensitivity, urinary incontinence, cystitis, burns,psoriasis, eczema, emesis, stomach duodenal ulcer and pruritus. Theconnection between therapeutic effect and inhibition of TRPA1 isillustrated, for example, in Story, G. M. et al. Cell, 2003, 112,819-829; McMahon, S. B. and Wood, J. N., Cell, 2006, 124, 1123-1125;Voorhoeve, P. M. et al. Cell, 2006, 124 1169-1181; Wissenbach, U,Niemeyer, B. A. and Flockerzi, V. Biology of the Cell, 2004, 96, 47-54;and the references cited therein.

Pain can be acute or chronic. While acute pain is usually self-limiting,chronic pain persists for 3 months or longer and can lead to significantchanges in a patient's personality; lifestyle, functional ability andoverall quality of life (K. M. Foley, Pain, in Cecil Textbook ofMedicine; J. C. Bennett & F. Plum (eds.), 20th ed., 1996, 100-107). Thesensation of pain can be triggered by any number of physical or chemicalstimuli and the sensory neurons which mediate the response to thisharmful stimulus are termed as “nociceptors”. Nociceptors are primarysensory afferent (C and Aδ fibers) neurons that are activated by a widevariety of noxious stimuli including chemical, mechanical, thermal andproton (pH<6) modalities. Nociceptors are the nerves which sense andrespond to parts of the body which suffer from damage. They signaltissue irritation, impending injury, or actual injury. When activated,they transmit pain signals (via the peripheral nerves as well as thespinal cord) to the brain.

Chronic pain can be classified as either nociceptive or neuropathic.Nociceptive pain includes tissue injury-induced pain and inflammatorypain such as that associated with arthritis. Neuropathic pain is causedby damage to the sensory nerves of the peripheral or central nervoussystem and is maintained by aberrant somatosensory processing. The painis typically well localized, constant and often with an aching orthrobbing quality. Visceral pain is the subtype of nociceptive pain thatinvolves the internal organs. It tends to be episodic and poorlylocalized. Nociceptive pain is usually time limited, meaning when thetissue damage heals, the pain typically resolves (arthritis is a notableexception in that it is not time limited).

General Methods of Preparation

The compounds of the general formula (I), (Ia), (Ib) and (Ic) andspecific examples to demonstrate embodiments of the invention can beprepared by methods described below in Schemes 1-8. However, thoseskilled in the art should, in light of the methods described herein, canprepare these compounds through similar approaches without departingfrom the spirit and scope of the invention. Furthermore, in thefollowing synthetic schemes, where specific acids, bases, reagents,coupling agents, solvents, etc. are mentioned, it is understood thatother suitable acids, bases, reagents, coupling agents etc. may be usedand are included within the scope of the present invention. Thecompounds obtained by using the general reaction sequences may be ofinsufficient purity. These compounds can be purified by using any of themethods for purification of organic compounds known to persons skilledin the art, for example, crystallization or silica gel or alumina columnchromatography using different solvents in suitable ratios. All possiblestereoisomers are envisioned within the scope of this invention.

A general approach for the synthesis of furopyrimidinyl acetamides ofthe general formula (I), wherein Z₁, Z₂, R¹, R², R³, U, V and L are asdefined above in description is prepared as described in Scheme 1.Coupling reaction of the compounds of the formula (1) (wherein R ishydrogen or alkyl) with amines of the formula (2) in the presence of asuitable coupling agent such as1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) andbase in suitable solvent gives compounds of the formula (3). Theselective N-alkylation of the compounds of the formula (3) where X ishalogen, with suitable alkylating agent of the formula (4) in thepresence of base in a suitable solvent gives compounds of the generalformula (1).

A general approach for the synthesis of furo[2,3-d]pyrimidinylacetamides of formula (Ia) wherein R^(a) is hydrogen and U, V, R¹ and R²are as defined above is prepared as shown is Scheme 2. Coupling reactionof 1,3-dialkylbarbituric acid derivative of the formula (5) withchloroacetyl chloride derivative (6) in the presence of a suitable baselike sodium hydride and in a suitable solvent like THF gives5-(chloroacetyl)-6-hydroxy-1,3-dialkylpyrimidine-2,4(1H,3H)-dione as anintermediate which on cyclisation in the presence of triethylamine givesfuro[2,3-d]pyrimidinetrione of formula (7). A similar approach isdescribed by Strekowski, L. et al. in J. Heterocyclic Chem. 2001, 38,359-363. Furo[2,3-d]pyrimidinetrione compounds of formula (7) wasconverted into furo[2,3-d]pyrimidinedione ester of compounds of generalformula (8) by reaction with the lithium salt of ethyl acetate(generated from dry ethyl acetate and Lithium bis(trimethylsilyl)amide[LHMDS]) followed by dehydration and isomerization under acidicconditions. Direct coupling of compounds of the general formula (8) withappropriate amines of formula (2) by using suitable base (e.g., sodiumhydride) and in suitable solvent (e.g. toluene, tetrahydrofuran) givescompounds of the general formula (Ia). Alternatively, compounds of thegeneral formula (Ia) can be prepared in two steps by hydrolysis of (8)under basic conditions to give the carboxylic acid (9) followed bycoupling with amine of the general formula (2) using a suitable couplingagents [e.g., N-ethyl-N′-(3-dimethylaminopropyl) carbodiimidehydrochloride (EDCI), benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate [BOP] in suitable solvent or mixture ofsolvents (e.g., N,N-dimethyl formamide, tetrahydrofuran, dichloromethaneetc. to give compounds of the general formula (Ia).

Alternatively, the carboxylic acid intermediate of the general formula(9) can be prepared as described in scheme 3. Thus, reaction ofcyanomethyl lithium with furo[2,3-d]pyrimidinetrione of formula (7)(where R^(a) is hydrogen or alkyl) in a suitable solvent givesfuro[2,3-d]pyrimidinyl acetonitrile of the formula (10). Thisintermediate on hydrolysis under acidic conditions gives intermediatesof the formula (9) required for the synthesis of compounds of thegeneral formula (Ia).

Furo[2,3-d]pyrimidinedione ester of the formula (8a) where R^(a) ishydrogen or alkyl can also be prepared through a Wittig reaction onintermediate (7) as shown in Scheme 4. Thus, reaction of intermediate(7) with trimethyl phosphonoacetate in the presence of a suitable basesuch as sodium hydride, potassium tert-butoxide or n-butyl lithium insuitable solvent (e.g., tetrahydrofuran, dimethhyl sulfoxide) givesester of the formula (11). The ester (11) is then isomerized underacidic conditions to give intermediates of the formula (8a) useful forthe preparation of compounds of the present invention represented by theformula (Ia).

Another approach for the preparation of intermediates of the generalformula (8b) is given in Scheme 5. Thus, Reformatsky reaction onintermediate (7) (where R^(a) is hydrogen or alkyl) by using BrZnCH₂CO₂Rwhere R is alkyl (prepared from Zn and BrCH₂CO₂R) followed by in-situdehydration of the carbinol intermediate gives intermediate (12). Doublebond isomerization of intermediate (12) under acidic conditions givesthe ester intermediate (8b).

General approach for the synthesis of compound of formula (Ic) (whereinR^(a) is hydrogen or methyl and R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are asdefined above) is depicted in scheme 6. Direct coupling of compounds ofthe general formula (8) with appropriate amines of formula (23) by usingsuitable base (e.g., sodium hydride) and in suitable solvent (e.g.toluene, tetrahydrofuran) gives compounds of the general formula (Ic).Alternatively, compounds of the general formula (Ic) can be prepared intwo steps by hydrolysis of (8) under basic conditions to give thecarboxylic acid (9) followed by its coupling with amine of the generalformula (23) using a suitable coupling agents [e.g.,N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI),benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate[BOP]) in suitable solvent or mixture of solvents (e.g., N,N-dimethylformamide, tetrahydrofuran, dichloromethane etc. to give compounds ofthe general formula (Ic).

A general approach for the synthesis of furo[3,4-d]pyrimidinylacetamides of formula (Ib) wherein R^(a), U, V, R¹ and R² are as definedabove is prepared as shown is Scheme 7.5-Methyl-4H-furo[3,4-d][1,3]oxazine-2,4(1H)-dione of the formula (13)can be prepared according to the procedure described by Press, J. B., etal. Eur. J. Med. Chem. 1989, 24, 627-630 starting from dialkyl2-methylfuran-3,4-dicarboxylate. The intermediate of the formula (1) istreated with alkyl amine of the formula R¹—NH₂ to give the ureaderivative (14) through a ring opening reaction. Cyclisation ofintermediate (14) using 1,1′-carbonyldiimidazole (CDI) in suitablesolvent followed by alkylation with R²X in the presence of a suitablesolvent gives 3,5-dialkylfuro[3,4-d]pyrimidine-2,4(1H,3H)-dione of theformula (16) via intermediate (15). Intermediate (16) is deprotonatedwith a strong base such as sodium hydride or n-butyl lithium and reactedwith dialkyl carbonate to give the ester (17). Coupling reaction ofester of the formula (17) with appropriate amines of formula (2) in thepresence of a suitable base such as sodium hydride in the presence ofsuitable solvent such as dry toluene or xylene gives compounds ofgeneral formula (Ib).

A general approach for the synthesis of substituted 2-amino-4-arylthiazoles of the formula (23) (wherein R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are asdefined above) from benzoic acid derivatives is given in Scheme 8. Thus,benzoic acid of formula (18) was converted to the corresponding acidchloride of formula (19) using oxalyl chloride in the presence ofcatalytic amounts of DMF in dry dichloromethane. The acid chloride offormula (19) was converted to corresponding Weinerb amide of formula(21) by treating with N,O-dimethylhydroxylamine hydrochloride of formula(20) in the presence of a suitable base such as triethylamine. Theaddition of methyl magnesium iodide to Weinreb amide of formula (21)afforded acetophenone derivative of formula (22).

Conversion of acetophenone derivative of formula (22) to 2-amino-4-arylthiazole of the formula (23) can be effected by two approaches (Scheme8). In the first case acetophenone was converted to the correspondingphenacyl bromide, which in turn was reacted with thiourea in a suitablesolvent such as tetrahydrofuran at refluxing condition. Alternatively,acetophenone derivative of formula (22) can be converted to2-amino-4-aryl thiazole (23) in one step by its reaction with thioureaand iodine in refluxing ethanol (Carroll, K. et al. J. Am. Chem. Soc.1950, 3722 and Naik, S. J.; Halkar, U. P., ARKIVOC 2005, xiii, 141-149).

EXPERIMENTAL

Unless otherwise stated, work-up includes distribution of the reactionmixture between the organic and aqueous phase indicated withinparentheses, separation of layers and drying the organic layer oversodium sulphate, filtration and evaporation of the solvent.Purification, unless otherwise mentioned, includes purification bysilica gel chromatographic techniques, generally using ethylacetate/petroleum ether mixture of a suitable polarity as the mobilephase. Use of a different eluent system is indicated within parentheses.The following abbreviations are used in the text: DMSO-d₆:Hexadeuterodimethyl sulfoxide; DMF: N,N-dimethylformamide; J: Couplingconstant in units of Hz; RT or rt: room temperature (22-26° C.); Aq.:aqueous; AcOEt: ethyl acetate; equiv. or eq.: equivalents.

INTERMEDIATES Intermediate 1 Ethyl(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetate

Step 1 Ethyl(2Z)-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5(6H)-ylidene)acetateOR Ethyl(5-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,6-hexahydrofuro[2,3-d]pyrimidin-5-yl)acetate:Anhydrous THF (50.0 ml) was cooled to −78° C. A solution of lithiumbis(trimethylsilyl)amide (LiHMDS) (1.0 M in THF, 4.692 g, 28.038 mmol)was added under nitrogen atmosphere. Then, dry ethyl acetate (2.358 g,26.763 mmol) was added and the resulting mixture was stirred at the sametemperature for 1 h. A solution of1,3-dimethylfuro[2,3-d]pyrimidine-2,4,5(1H,3H,6H)-trione (5.0 g, 25.489mmol) in a mixture of THF and dichloromethane (1:3, 80.0 ml) was addeddropwise to the above solution and the resulting mixture was stirred at−78° C. for 2.5 h. The reaction mixture was then acidified with 1N HCl(75.0 ml). The temperature was allowed to rise gradually until reachingroom temperature and was extracted with ethyl acetate. The organicextracts were washed with brine (50.0 ml), dried over anhydrous Na₂SO₄and filtered. The filtrate was evaporated under reduced pressure and theresidue obtained was purified with column chromatography by using 2%methanol in chloroform to obtain 2.1 g of ethyl(2Z)-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5(6H)-ylidene)acetateas a white solid; ¹H NMR (300 MHz, CDCl₃) δ 1.29 (t, J=7.2 Hz, 3H), 3.35(s, 3H), 3.45 (s, 3H), 4.17 (q, J=7.5 Hz, 2H), 6.37 (s, 1H). Furtherelution with increasing amounts of methanol in chloroform gives 750 mgof ethyl(5-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,6-hexahydrofuro[2,3-d]pyrimidin-5-yl)acetateas a light brown solid; ¹H NMR (300 MHz, CDCl₃) δ 1.33 (t, J=7.2 Hz,3H), 3.39 (s, 3H), 3.54 (s, 3H), 4.08 (s, 2H), 4.27 (q, J=7.5 Hz, 2H),4.77 (s, 1H); APCI-MS (m/z) 267.09 (M+H)⁺.

Step 2 Ethyl(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetate:A mixture of Step 1 intermediate (1.1 g, 4.131 mmol) and glacial aceticacid (20.0 ml) was refluxed for 4 h. Excess of acid was evaporated undervacuum and the residue obtained after evaporation of the solvent waspurified by silica gel column chromatography using 2% methanol inchloroform to obtain 930 mg of the product as a white solid; ¹H NMR (300MHz, CDCl₃) δ 1.19 (t, J=7.5 Hz, 3H), 3.18 (s, 3H), 3.41 (s, 3H), 3.68(s, 2H), 4.09 (q, J=7.2 Hz, 2H), 7.58 (s, 1H); APCI-MS (m/z) 267.13(M+H)⁺.

Intermediate 2 (359-NPP-182)(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)aceticacid

To a stirred solution of Intermediate 1 (150 mg, 0.563 mmol) in amixture of THF (2.0 ml) and water (1.0 ml) was added LIOH.H₂O (36 mg,0.845 mmol). The mixture was stirred for 30 min. at room temperature.Residue obtained after evaporation of the solvent was acidified with 1 NHCl (pH 4) and extracted with ethyl acetate (2×50 ml). The combinedethyl acetate extracts were washed with water (2×15 ml) and dried(Na₂SO₄). Evaporation of solvent under reduced pressure afforded 70 mgof the product as an off-white solid; ¹H NMR (300 MHz, CDCl₃) δ 3.19 (s,3H), 3.50 (s, 3H), 3.60 (s, 2H), 7.56 (s, 1H), 12.43 (br s, 1H); APCI-MS(m/z) 239.06 (M+H)⁺.

Intermediate 3 (359-NPP-186)

Ethyl(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetate

The title compound was prepared according to the procedure described inIntermediate 1 by using1,3,6-trimethylfuro[2,3-d]pyrimidine-2,4,5(1H,3H,6H)-trione (5.0 g,23.788 mmol) in the place of1,3-dimethylfuro[2,3-d]pyrimidine-2,4,5(1H,3H,6H)-trione in the firststep to give 1.565 g of the product as a white solid; ¹H NMR (300 MHz,CDCl₃) δ 1.28 (t, J=7.5 Hz, 3H), 2.28 (s, 3H), 3.35 (s, 3H), 3.52 (s,3H), 3.64 (s, 2H), 4.19 (q, J=7.2 Hz, 2H); APCI-MS (m/z) 281.05 (M+H)⁺.

Intermediate 4 (394-NPP-003)(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)aceticacid

Saponification of Intermediate 3 (150 mg, 0.535 mmol) using LiOH (34 mg,0.802 mmol) in a mixture of THF (4.0 ml) and water (1.0 ml) as describedin Intermediate 2 afforded 60 mg of the title compound as a white solid;¹H NMR (300 MHz, CDCl₃) δ 2.27 (s, 3H), 3.17 (s, 3H), 3.39 (s, 3H), 3.55(s, 2H), 12.32 (br s, 1H); APCI-MS (m/z) 253.09 (M+H)⁺.

General procedure for the preparation of 2-amino-4-aryl thiazoles:

Method 1

A solution of acetophenone derivative (1.0 equiv) in glacial acetic acid(5 vol) was added liquid bromine (1.0 equiv) at 0° C. and reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas diluted with water and extracted with ethyl acetate, washed withbrine and dried over Na₂SO₄. The crude product obtained uponconcentration was dissolved in dry THF (10 volumes) and thiourea (2.0equiv) was added and refluxed overnight. The reaction mixture wasdiluted with ethyl acetate, washed with sodium thiosulfate solution andorganic layer was treated with 1N HCl to result in salt formation of theamine. The precipitated salt was collected by filtration. The salt wasthen treated with saturated solution of NaHCO₃ to re-generate the amine.The mixture was extracted with dichloromethane (2×50 ml) and thecombined organic extracts were washed with water and brine. The solventwas evaporated under reduced pressure to afford the 2-amino-4-arylthiazole derivative.

Method 2

A solution of acetophenone derivative (1.0 equiv.), thiourea (2.0equiv.) and iodine (1.0 equiv.) in dry ethanol (5 volumes) was refluxedfor 24 h. The reaction mixture was diluted with ethyl acetate and thelayers were separated. The organic layer was washed with sodiumthiosulfate solution to remove iodine. The ethyl acetate solution wastreated with 1N HCl and precipitated salt collected by filtration. Thefree amine was re-generated as described in Method 1 given above.

All the 2-amino-4-aryl thiazole derivatives were prepared by eitherMethod 1 or Method 2 starting from appropriate aryl alkyl ketones.Structure information and characterization data for selectedintermediates are given in Table 1.

TABLE 1 Structural details and ¹H NMR data of selected 2-aminothiazoleintermediates Sr. Mol. Formula No. Structure (Mol. Wt.) ¹H NMR (δ ppm,300 MHz)  1.

C₄H₃F₃N₂S 168.14 DMSO-d₆: 7.26 (s, 1H), 7.42 (br. s, 2H)  2.

C₁₃H₁₆N₂S 232.25 DMSO-d₆: 0.86 (d, J = 6.6 Hz, 6H), 1.86-1.76 (m, 1H),2.43 (d, J = 6.9 Hz, 2H), 6.92 (s, 1H), 7.03 (br s, 2H), 7.13 (d, J =8.1 Hz, 2H), 7.68 (d, J = 7.8 Hz, 2H)  3.

C₁₀H₇F₃N₂S 244.24 DMSO-d₆: 7.16 (br s, 2H), 7.24 (s, 1H), 7.69 (d, J =8.1 Hz, 2H), 7.97 (d, J = 7.8 Hz, 2H)  4.

C₁₀H₇F₃N₂S 244.24 CDCl₃: 5.02 (br. s, 2H), 6.79 (s, 1H), 7.50-7.42 (m,2H), 7.91 (d, J = 6.9 Hz, 1H), 8.12-8.06 (m, 1H)  5.

C₁₃H₁₆N₂S 260.24 CDCl₃: 7.09 (s, 1H), 7.13 (br. s, 2H), 7.35 (d, J =8.4, 2H); 7.90 (d, J = 8.1, 2H).  6.

C₁₀H₆F₄N₂S 262.24 CDCl₃: 5.08 (br s, 2H), 6.75 (s, 1H), 7.10 (d, J = 7.8Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.68-7.61 (m, 2H)  7.

C₉H₆BrFN₂S 273.13 DMSO-d₆: 7.12-7.18 (m, 1H + 2H), 7.37 (t, J = 9.0 Hz,1H), 7.80-7.86 (m, 1H), 8.06-8.12 (m, 1H)  8.

C₉H₆F₂N₂S 212.22 CDCl₃: 4.98 (br s, 2H), 6.66 (s, 1H), 7.18-7.07 (m,1H), 7.48-7.43 (m, 1H), 7.60-7.53 (m, 1H)  9.

C₂H₆F₂N₂S 212.22 CDCl₃: 5.04 (br s, 2H), 6.93-6.80 (m, 3H), 8.04-7.95(m, 1H) 10.

C₉H₆Cl₂N₂S 245.13 CDCl₃:7.85 (s, 1H); 7.56 (dd, J = 8.4 Hz, 2.1, 1H);7.39 (d, J = 8.4 Hz, 1H); 6.72 (s, 1H); 5.01 (br s, 2H). 11.

C₁₀H₆F₄N₂S 262.23 DMSO-d₆: 7.24 (br s, 2H), 7.40 (s, 1H), 7.88-7.73 (m,3H) 12.

C₁₀H₆F₄N₂S 262.23 DMSO-d₆: 7.20 (br. s, 2H), 7.24 (s, 1H), 7.52 (t, J =8.7 Hz, 1H), 8.13 (d, J = 6.0 Hz, 2H) 13.

C₁₁H₈F₄N₂S 276.25 DMSO-d₆: 2.34 (s, 3H), 6.92 (br s, 2H), 7.53 (t, J =9.6 Hz, 1H), 7.88-7.94 (m, 2H) 14.

C₁₀H₆F₄N₂OS 278.23 DMSO-d₆: 7.18 (br. s, 3H), 7.50 (t, J = 8.7 Hz, 1H),7.92-7.85 (m, 2H) 15.

C₁₀H₆F₄N₂OS 278.23 DMSO-d₆: 7.18 (br. s, 2H), 7.24 (s, 1H), 7.55 (d, J =8.1 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.87-7.80 (m, 1H) 16.

C₉H₆Cl₂N₂S 245.13 CDCl₃: 5.01 (br. s, 2H), 6.72 (s, 1H), 7.39 (d, J =8.4 Hz, 1H), 7.56 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 7.85 (s, 1H) 17.

C₉H₆Cl₂N₂S 245.13 CDCl₃: 5.02 (br s, 2H), 7.26 (s, 1H); 7.06 (s, 1H),7.42 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H) 18.

C₉H₆Cl₂N₂S 245.13 DMSO-d₆: 7.04-7.08 (m, 1H + 2H), 7.38 (t, J = 7.8 Hz,1H), 7.58 (d, J = 6.9 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H) 19.

C₁₀H₆ClF₃N₂S 278.68 CDCl₃: 5.05 (br. s, 2H), 6.78 (s, 1H), 7.46 (d, J =8.1 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 8.08 (s, 1H) 20.

C₁₀H₆ClF₃N₂OS 278.68 DMSO-d₆: 7.20 (br s, 2H), 7.27 (s, 1H), 7.67 (d, J= 8.4 Hz, 1H), 7.82-7.91 (m, 2H) 21.

C₁₀H₆F₄N₂S 262.23 CDCl₃: 5.04 (br s, 2H), 7.10 (s, 1H), 7.27 (t, J = 7.5Hz, 1H), 7.51 (t, J = 6.9 Hz, 1H), 8.28-8.21 (m, 1H) 22.

C₁₀H₆F₄N₂OS 263.23 DMSO-d₆: 7.23 (br. s, 2H), 7.41 (s, 1H), 7.62-7.52(m, 1H), 7.97-7.87 (m, 1H) 23.

C₁₀H₆F₄N₂S 262.23 CDCl₃: 7.13 (s, 1H), 7.26 (br. s, 2H), 7.58-7.50 (m,1H), 7.73-7.65 (m, 1H), 8.36-8.29 (m, 1H) 24.

C₁₀H₆F₄N₂S 262.23 CDCl₃: 5.00 (br. s, 2H), 7.13 (s, 1H), 7.37-7.30 (m,1H), 7.42 (d, J = 7.8 Hz, 1H), 8.15 (t, J = 7.2 Hz, 1H) 25.

C₁₀H₆ClF₃N₂S 278.68 DMSO-d₆: 7.25 (br. s, 2H), 7.46 (s, 1H), 7.73 (s,1H), 8.10 (s, 1H), 8.17 (s, 1H) 26.

C₁₀H₆ClF₃N₂S 278.68 DMSO-d₆: 7.25 (br s, 2H), 7.43 (s, 1H), 7.84 (d, J =8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 8.09 (s, 1H) 27.

C₁₀H₆ClF₃N₂OS 293.98 DMSO-d₆: 7.19 (br s, 2H), 7.57 (d, J = 8.1 Hz, 1H),7.86 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H) 28.

C₁₀H₆ClF₃N₂OS 293.98 DMSO-d₆: 7.21 (br s, 2H), 7.36 (s, 1H), 7.41 (s,1H), 7.72 (s, 1H), 7.90 (s, 1H) 29.

C₁₀H₇F₃N₂OS 260.24 DMSO-d₆: 7.12 (br s, 3H), 7.23 (t, J = 73.2 Hz, 1H),7.33 (t, J = 8.1 Hz, 1H), 7.75-7.62 (m, 2H) 30.

C₁₀H₇ClF₂N₂OS 275.99 DMSO-d₆: 6.94 (s, 1H), 7.04-7.15 (m, 3H), 7.61-7.51(m, 2H) 31.

C₁₀H₇BrF₂N₂OS 321.14 DMSO-d₆: 7.13 (br s, 3H), 7.28 (t, J = 73.2 Hz,1H), 7.33 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 8.13 (s, 1H)32.

C₁₄H₁₇FN₂OS 280.36 DMSO-d₆: 1.00 (s, 9H), 3.71 (s, 2H), 6.95 (s, 1H),7.05 (br s, 2H), 7.15 (t, J = 8.7 Hz, 1H), 7.52-7.62 (m, 2H) 33.

C₁₄H₁₇ClN₂OS 296.82 DMSO-d₆: 1.03 (s, 9H), 3.72 (s, 2H), 6.97 (s, 1H),7.07-7.15 (m, 1H + 2H), 7.70 (d, J = 9.0 Hz, 1H), 7.84 (s, 1H) 34.

C₁₄H₁₇BrN₂OS 341.27 DMSO-d₆: 1.04 (s, 9H), 3.37 (s, 2H), 7.00 (s, 1H),7.05 (br s, 2H), 7.70-7.76 (m, 2H), 7.99 (s, 1H) 35.

C₁₁H₈F₄N₂OS 292.25 CDCl₃: 7.57-7.46 (m, 2H), 7.02 (t, J = 8.4, 1H); 6.66(s, 1H); 5.08 (br s, 2H); 4.43 (q, J = 8.4 Hz, 2H) 36.

C₁₁H₈ClF₃N₂OS 308.71 DMSO-d₆: 4.88 (q, J = 8.7 Hz, 2H), 7.07-7.11 (m,1H + 2H), 7.27 (d, J = 8.7 Hz, 1H), 7.75 (d, J = 6.9 Hz, 1H), 7.89 (s,1H) 37.

C₁₁H₈BrF₃N₂OS 353.16 DMSO-d₆: 4.87 (q, J = 8.7 Hz, 2H), 7.07-7.15 (m,1H + 2H), 7.23 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 6.9 Hz, 1H), 8.05 (s,1H) 38.

C₉H₅Cl₃N₂S 297.57 DMSO-d₆: 7.10-7.18 (m, 1H + 2H), 7.67 (d, J = 9.0 Hz,1H), 7.79 (d, J = 8.7 Hz, 1H) 39.

C₉H₅ClF₂N₂S 245.98 DMSO-d₆: 7.01 (s, 1H), 7.19 (br s, 2H), 7.365 (t, J =8.7 Hz, 1H), 7.95 (q, J = 6.9 Hz, 1H) 40.

C₁₀H₅F₅N₂S 280.22 DMSO-d₆: 7.05 (s, 1H), 7.21 (br s, 2H), 7.43 (t, J =9.0 Hz, 1H), 8.35-8.23 (m, 1H) 41.

C₁₀H₅F₅N₂S 280.22 DMSO-d₆: 7.29 (br s, 2H), 7.52 (s, 1H), 7.72 (d, J =11.7 Hz, 2H) 42.

C₉H₅F₃N₂S 230.21 DMSO-d₆: 7.00 (s, 1H), 7.20 (br s, 2H), 7.55-7.67 (m,1H), 7.80-7.90 (m, 1H). 43.

C₁₀H₆F₄N₂OS 278.23 DMSO-d₆: 7.20 (br s, 2H), 7.24 (t, J = 72.3 Hz, 1H),7.48 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H) 44.

C₁₀H₆Cl₂F₂N₂OS 311.14 DMSO-d₆: 7.14 (t, J = 71.7 Hz, 1H), 7.20 (br s,2H), 7.33 (s, 1H), 7.56 (s, 2H). 45.

C₁₁H₇F₅N₂OS 310.24 DMSO-d₆: 4.82 (q, J = 9.0 Hz, 2H), 7.16 (br s, 2H),7.21 (s, 1H), 7.55 (s, 1H), 7.59 (s, 1H) 46.

C₁₂H₉F₅N₂OS 324.27 DMSO-d₆: 2.50 (s, 2H), 4.80 (q, J = 8.7 Hz, 2H),7.16-7.22 (m, 1H + 2H), 7.58 (d, J = 9.0 Hz, 1H) 47.

C₁₁H₇ClF₄N₂OS 326.70 DMSO-d₆: 4.80 (q, J = 8.7 Hz, 2H), 7.17 (br s, 2H),7.23 (s, 1H) 7.67-7.77 (m, 2H) 48.

C₁₁H₇Cl₂F₃N₂OS 343.15 DMSO-d₆: 4.72 (q, J = 8.7 Hz, 2H), 7.18 (br s,2H), 7.28 (s, 1H) 7.91 (s, 2H) 49.

C₁₄H₁₆F₂N₂OS 298.35 DMSO-d₆: 1.00 (s, 9H), 3.76 (s, 2H), 7.12-7.18 (m,1H + 2H), 7.48-7.58 (m, 2H) 50.

C₁₄H₁₆ClFN₂OS 314.81 DMSO-d₆: 1.02 (s, 9H), 3.74 (s, 2H), 7.12-7.18 (m,1H + 2H), 7.61-7.68 (m, 1H), 7.71 (s, 1H) 51.

C₁₃H₁₄F₂N₂OS 284.33 DMSO-d₆: 0.97 (d, J = 6.6 Hz, 6H), 1.94-2.00 (m,1H), 3.87 (d, J = 6.3 Hz, 2H), 7.12-7.18 (m, 1H + 2H), 7.22 (s, 1H),7.87 (s, 1H) 52.

C₁₃H₁₄Cl₂N₂OS 317.23 DMSO-d₆: 1.04 (d, J = 6.6 Hz, 6H), 1.98-2.14 (m,1H), 3.75 (d, J = 6.3 Hz, 2H), 7.12-7.18 (m, 1H + 2H), 7.50 (s, 1H),7.55 (s, 1H) 53.

C₁₄H₁₆Cl₂N₂OS 331.26 DMSO-d₆: 1.07 (s, 9H), 3.67 (s, 2H), 7.90 (s, 1H),7.99 (s, 2H), 12.72 (br s, 2H) 54.

C₁₃H₁₂F₂N₂OS 282.31 CDCl₃: 0.31-0.25 (m, 2H), 0.61-0.56 (m, 2H),1.28-1.22 (m, 1H), 3.97 (d, J = 6.9 Hz, 2H), 5.01 (br s, 2H), 6.66 (s,1H), 7.29 (s, 1H), 7.33 (s, 1H) 55.

C₁₄H₁₆F₂N₂OS 298.35 DMSO-d₆: 0.92 (d, J = 6.6 Hz, 6H), 1.58 (q, J = 6.6Hz, 2H), 1.75-1.83 (m, 1H), 4.08-4.15 (m, 2H), 7.10-7.16 (m, 3H),7.48-7.55 (m, 2H) 56.

C₉H₅F₃N₂S 230.21 DMSO-d₆: 7.16-7.21 (m, 1H + 2H), 7.63-7.73 (m, 2H) 57.

C₉H₅F₃N₂S 230.21 DMSO-d₆: 6.99 (s, 1H), 7.20 (br s, 2H), 7.35 (q, J =9.3 Hz, 1H), 7.33 (q, J = 6.6 Hz, 1H) 58.

C₉H₅Cl₂FN₂S (263.12) CDCl₃: 4.97 (br s, 2H), 7.19 (s, 1H), 7.44 (d, J =6.9 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H)

Further it should also be noted that several fluoro substituted2-amino-4-aryl thiazoles can be prepared using the approach described inScheme 8 by following Method 1 or

Method 2 starting from appropriate fluorinated benzoic acid orfluorinated acetophenone. A few examples of such aminothiazoleintermediates are given in Table 2.

TABLE 2 Structure of fluoro substituted 2-amino-4-arylthiazoles Mol.(Mol. S No Structure Name Formula Wt.)  1.

4-[2,6-difluoro-4- (trifluoromethyl)phenyl]- 1,3-thiazol-2-amineC₁₀H₅F₅N₂S 280.22  2.

4-[2,5-difluoro-4- (trifluoromethoxyphenyl]- 1,3-thiazol-2-amineC₁₀H₅F₅N₂OS 296.22  3.

4-[2,5-difluoro-4- (difluoromethoxyphenyl]- 1,3-thiazol-2-amineC₁₀H₆F₄N₂OS 278.23  4.

4-[2,5-difluoro-4- (trifluoromethyl)phenyl]- 1,3-thiazol-2-amineC₁₀H₅F₅N₂S 280.22  5.

4-[2,3-difluoro-5- (trifluoromethyl)phenyl]- 1,3-thiazol-2-amineC₁₀H₅F₅N₂S 280.22  6.

4-[2,5-difluoro-3- (trifluoromethyl)phenyl]- 1,3-thiazol-2-amineC₁₀H₅F₅N₂S 280.22  7.

4-[2,4-difluoro-5- (trifluoromethyl)phenyl]- 1,3-thiazol-2-amineC₁₀H₅F₅N₂S 280.22  8.

4-[2,6-difluoro-3- (trifluoromethyl)phenyl]- 1,3-thiazol-2-amineC₁₀H₅F₅N₂S 280.22  9.

4-[2,3-difluoro-4- (trifluoromethyl)phenyl]- 1,3-thiazol-2-amineC₁₀H₅F₅N₂S 280.22 10.

4-[2,4-difluoro-3- (trifluoromethoxy)phenyl]- 1,3-thiazol-2-amineC₁₀H₅F₅N₂OS 296.22 11.

4-[2,3-difluoro-4- (trifluoromethoxy)phenyl]- 1,3-thiazol-2-amineC₁₀H₅F₅N₂OS 296.22 12.

4-[2-fluoro-4- (trifluoromethoxy)phenyl]- 1,3-thiazol-2-amineC₁₀H₆F₄N₂OS 278.23 13.

4-[2,4-difluoro-3- (difluoromethoxy)phenyl]- 1,3-thiazol-2-amineC₁₀H₆F₄N₂OS 278.23 14.

4-[2,3-difluoro-4- (difluoromethoxy)phenyl]- 1,3-thiazol-2-amineC₁₀H₆F₄N₂OS 278.23 15.

4-[2-fluoro-4- (difluoromethoxy)phenyl]- 1,3-thiazol-2-amine C₁₀H₇F₃N₂OS260.24For further illustration of methods of preparing the compounds of thepresent invention, the following examples are disclosed below.

EXAMPLES General Procedure

Method A:

To a stirred solution of appropriate amine (1.2 equiv.) in dry toluene,sodium hydride (1.4 equiv.) was added and after stirring for 30 min atroom temperature, furopyrimidinyl acetic acid ester derivative (1.0equiv.) was added and heated to reflux for 48 h. The reaction mixturewas concentrated and the residue obtained was acidified to pH 6.0 byaddition of 1 N hydrochloric acid and extracted with ethyl acetate. Thecombined organic layers were dried (Na₂SO₄). The residue obtained afterevaporation of the solvent was purified by silica gel columnchromatography using suitable ethyl acetate and petroleum ether mixtureto obtain the desired products.

Method B:

To a stirred solution of furopyrimidinyl acetic acid derivative (1.0equiv.) in 1,2-dichloroethane (5 vol.) was added EDCI (1.2 equiv.), HOBt(0.3 equiv.) and 4-dimethylaminopyridine (0.1 equiv.) and the mixturewas stirred at room temperature for 10-15 min. An appropriate amine (1.0equiv.) was then added and mixture was stirred at the same temperaturefor 48 h. Excess of solvent was evaporated and the residue obtained wasdiluted with ethyl acetate and 2 N HCl. Two layers were seperated. Theorganic layer was washed with water, brine, dried (Na₂SO₄) and filtered.The filtrate was concentrated under reduced pressure and the residueobtained was purified by silica gel column chromatography using 30%ethyl acetate in petroleum ether to afford the desired compound.

Example 1

N1-[4-(4-Trifluoromethylphenoxy)phenyl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method B) by coupling Intermediate 2 (60 mg, 0.252 mmol) with4-[4-(trifluoromethyl)phenoxy]aniline (64 mg, 0.252 mmol) in thepresence of EDCI hydrochloride (58 mg, 0.302 mmol), HOBt (10 mg, 0.075mmol) and DMAP (3.1 mg, 0.025 mmol) in 1,2-dichloroethane (5 ml) to give17 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.20(s, 3H), 3.43 (s, 3H), 3.74 (s, 2H), 7.06-7.13 (m, 4H), 7.60-7.73 (m,5H), 10.27 (br s, 1H); APCI-MS (m/z) 474.40 (M+H)⁺.

Example 2N1-[2-(2,4-Dichlorophenyl)ethyl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method B) by coupling Intermediate 2 (100 mg, 0.420 mmol) with2-(2,4-dichlorophenyl)ethanamine (79 mg, 0.415 mmol) in the presence ofEDCI hydrochloride (96 mg, 0.504 mmol), HOBt (17 mg, 0.126 mmol) andDMAP (5 mg, 0.042 mmol) in 1,2-dichloroethane (5 ml) to give 10 mg ofthe product as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 2.81 (t, J=6.6Hz, 2H), 3.18 (s, 3H), 3.40-3.46 (m, 7H), 7.28 (s, 2H), 7.52 (d, J=8.7Hz, 2H), 8.02 (br s, 1H); APCI-MS (m/z) 410.21 (M+H)¹.

Example 3N1-[4-(Trifluoromethyl)-1,3-thiazol-2-yl]-2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-(trifluoromethyl)-1,3-thiazol-2-amine (60 mg, 0.360 mmol) in thepresence of sodium hydride (30 mg, 0.750 mmol) in dry toluene (10 ml) togive 40 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 3.17 (s, 3H), 3.42 (s, 3H), 3.87 (s, 2H), 7.63 (s, 1H), 7.95(s, 1H), 12.77 (br s, 1H); APCI-MS (m/z) 388.99 (M+H)¹.

Example 4N-(4,6-Difluoro-1,3-benzothiazol-2-yl)-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.375 mmol) with4,6-difluoro-1,3-benzothiazol-2-amine (83 mg, 0.450 mmol) in thepresence of sodium hydride (30 mg, 0.750 mmol) in dry toluene (10 ml) togive 8 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.92 (s, 2H), 7.39 (t, J=9.6 Hz,1H), 7.65 (s, 1H), 7.79 (d, J=7.8 Hz, 1H), 12.85 (br s, 1H); APCI-MS(m/z) 407.11 (M+H)⁺.

Example 5

N1-[4-(4-Isobutylphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-(4-isobutylphenyl)-1,3-thiazol-2-amine (84 mg, 0.360 mmol) in thepresence of sodium hydride (30 mg, 0.750 mmol) in dry toluene (10 ml) togive 25 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 0.88 (d, J=6.3 Hz, 6H), 1.82-1.90 (m, 1H), 3.18 (s, 3H), 3.43(s, 3H), 3.87 (s, 2H), 7.21 (d, J=7.8 Hz, 2H), 7.54 (s, 1H), 7.63 (s,1H), 7.81 (d, J=7.8 Hz, 2H), 12.44 (br s, 1H); APCI-MS (m/z) 453.16(M+H)⁺.

Example 6N1-{4-[4-(Trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (75 mg, 0.282 mmol) with4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (83 mg, 0.338 mmol) inthe presence of sodium hydride (28 mg, 0.705 mmol) in dry toluene (10ml) to give 20 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.89 (s, 2H), 7.64 (s, 1H),7.78-7.96 (m, 3H), 8.09-8.15 (m, 2H), 12.55 (br s, 1H); APCI-MS (m/z)465.11 (M+H)⁺.

Example 7N1-{4-[3-(Trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (88 mg, 0.360 mmol) inthe presence of sodium hydride (30 mg, 0.750 mmol) in dry toluene (10ml) to give 16 mg of the product as an off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.60-7.72 (m, 3H),7.88 (s, 1H), 8.20-8.26 (m, 2H), 12.54 (br s, 1H); APCI-MS (m/z) 465.32(M+H)⁺.

Example 8N1-[4-(4-Trifluorormethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (75 mg, 0.282 mmol) with4-[4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (88 mg, 0.338 mmol)in the presence of sodium hydride (28 mg, 0.705 mmol) in dry toluene (10ml) to give 11 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 3.18 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.43 (d, J=8.4 Hz,2H), 7.62 (s, 1H), 7.69 (s, 1H), 8.02 (d, J=9.0 Hz, 2H), 12.47 (br s,1H); APCI-MS (m/z) 481.14 (M+H)⁺.

Example 9N1-[4-(3-Trifluorormethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (93 mg, 0.360 mmol)in the presence of sodium hydride (36 mg, 0.900 mmol) in dry toluene (10ml) to give 60 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.33 (d, J=7.8 Hz,1H), 7.54-7.64 (m, 2H), 7.82 (s, 1H), 7.87 (s, 1H), 7.95 (d, J=7.8 Hz,1H), 12.52 (br s, 1H); ESI-MS (m/z) 481.21 (M+H)⁺.

Example 10N1-[4-(3-Bromo-4-fluorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-(3-bromo-4-fluorophenyl)-1,3-thiazol-2-amine (98 mg, 0.360 mmol) inthe presence of sodium hydride (36 mg, 0.900 mmol) in dry toluene (10ml) to give 16 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 3.18 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.45 (t, J=8.7 Hz,1H), 7.62 (s, 1H), 7.74 (s, 1H), 7.81-7.88 (m, 1H), 8.23 (d, J=6.9 Hz,1H), 12.45 (br s, 1H); APCI-MS (m/z) 491.36 (M−H)⁻.

Example 11N1-[4-(3,4-Difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-(3,4-difluorophenyl)-1,3-thiazol-2-amine (77 mg, 0.360 mmol) in thepresence of sodium hydride (30 mg, 0.750 mmol) in dry toluene (10 ml) togive 40 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.51 (q, J=8.7 Hz,1H), 7.63 (s, 1H), 7.70-7.76 (m, 2H), 7.87-7.96 (m, 1H), 12.49 (br s,1H); APCI-MS (m/z) 433.06 (M+H)⁺.

Example 12N1-[4-(2,4-Difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-(2,4-difluorophenyl)-1,3-thiazol-2-amine (76 mg, 0.360 mmol) in thepresence of sodium hydride (36 mg, 0.900 mmol) in dry toluene (10 ml) togive 29 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 3.18 (s, 3H), 3.40 (s, 3H), 3.86 (s, 2H), 7.20 (t, J=9.6 Hz,1H), 7.34-7.41 (m, 1H), 7.47 (s, 1H), 7.61 (s, 1H), 8.06 (q, J=7.5 Hz,1H), 12.53 (br s, 1H); APCI-MS (m/z) 433.05 (M+H)⁺.

Example 13N1-[4-(3,4-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.375 mmol) with4-(3,4-dichlorophenyl)-1,3-thiazol-2-amine (110 mg, 0.450 mmol) in thepresence of sodium hydride (30 mg, 0.750 mmol) in dry toluene (10 ml) togive 17 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ3.18 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.63 (s, 1H), 7.70 (d, J=8.1Hz, 1H), 7.83 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 8.14 (s, 1H), 12.48 (brs, 1H); APCI-MS (m/z) 463.20 (M−H)⁻.

Example 14N1-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.375 mmol) with4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (118 mg,0.450 mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 25 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.18 (s, 3H), 3.43 (s, 3H), 3.89 (s, 2H), 7.63(s, 1H), 7.86 (t, J=7.8 Hz, 1H), 7.92-8.02 (m, 3H), 12.55 (br s, 1H);APCI-MS (m/z) 481.25 (M−H)⁻.

Example 15N1-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.375 mmol) with4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (136 mg,0.518 mmol) in the presence of sodium hydride (36 mg, 0.900 mmol) in drytoluene (10 ml) to give 25 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.18 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H),7.55-7.65 (m, 2H), 7.84 (s, 1H), 8.23-8.29 (m, 2H), 12.51 (br s, 1H);APCI-MS (m/z) 481.27 (M−H)⁻.

Example 16N1-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.375 mmol) with4-[4-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (125 mg,0.450 mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 26 mg of the product as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 3.18 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.55-7.63(m, 2H), 7.79 (s, 1H), 7.97-8.05 (m, 2H), 12.49 (br s, 1H); ESI-MS (m/z)497.24 (M−H)⁻.

Example 17N1-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (56 mg, 0.210 mmol) with4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (70 mg,0.252 mmol) in the presence of sodium hydride (21 mg, 0.525 mmol) in drytoluene (10 ml) to give 37 mg of the product as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.62-7.69(m, 2H), 7.84 (s, 2H), 7.95-8.01 (m, 1H), 12.54 (br s, 1H); ESI-MS (m/z)497.26 (M+H)⁺.

Example 18N1-{4-[4-Chloro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.375 mmol) with4-[4-chloro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (126 mg,0.450 mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 26 mg of the product as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.58-7.64(m, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.92 (s, 1H), 8.20 (d, J=7.8 Hz, 1H),8.34 (s, 1H), 12.54 (br s, 1H); APCI-MS (m/z) 499.00 (M+H)⁺.

Example 19N1-{4-[4-Chloro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[4-chloro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (100 mg,0.360 mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 32 mg of the product as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 3.18 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.62 (s,1H), 7.76 (d, J=8.7 Hz, 1H), 7.87 (s, 1H), 7.93-8.04 (m, 2H), 12.51 (brs, 1H); APCI-MS (m/z) 513.23 (M−H)⁻.

Example 20N1-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (94 mg, 0.360mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 50 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.18 (s, 3H), 3.43 (s, 3H), 3.89 (s, 2H), 7.53(d, J=7.8 Hz, 1H), 7.63 (s, 1H), 7.68 (s, 1H), 7.77 (t, J=6.9 Hz, 1H),8.33 (t, J=7.5 Hz, 1H), 12.55 (br s, 1H); APCI-MS (m/z) 481.26 (M−H)⁻.

Example 21N1-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (94 mg, 0.360mmol) in the presence of sodium hydride (36 mg, 0.900 mmol) in drytoluene (10 ml) to give 25 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H),7.60-7.68 (m, 2H), 7.98-8.15 (m, 3H), 12.54 (br s, 1H); APCI-MS (m/z)481.24 (M−H)⁻.

Example 22N1-{4-[2-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (94 mg, 0.360mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 30 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.18 (s, 3H), 3.43 (s, 3H), 3.90 (s, 2H), 7.63(s, 1H), 7.73 (s, 2H), 7.78-7.84 (m, 1H), 8.23-8.29 (m, 1H), 12.56 (brs, 1H); APCI-MS (m/z) 483.07 (M+H)⁺.

Example 23N1-[4-(3-Fluoro-4-difluoromethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-(3-fluoro-4-difluoromethoxyphenyl)-1,3-thiazol-2-amine (95 mg, 0.360mmol) in the presence of sodium hydride (36 mg, 0.900 mmol) in drytoluene (10 ml) to give 10 mg of the product as an off-white solid; ¹F1NMR (300 MHz, DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.01(t, J=73.2 Hz, 1H), 7.44 (t, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.73-7.81 (m,2H), 7.85-7.91 (m, 1H), 12.49 (br s, 1H); APCI-MS (m/z) 479.23 (M−H)⁻.

Example 24N1-[4-(3-Chloro-4-difluoromethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3-chloro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-amine (99 mg, 0.360mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 50 mg of the product as an off-white solid; ¹F1NMR (300 MHz, DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.32(t, J=73.2 Hz, 1H), 7.45 (d, J=9.0 Hz, 1H), 7.63 (s, 1H), 7.77 (s, 1H),7.93 (d, J=8.7 Hz, 1H), 8.10 (s, 1H), 12.49 (br s, 1H); APCI-MS (m/z)497.16 (M+H)⁺.

Example 25N1-[4-(3-Bromo-4-difluoromethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3-bromo-4-(difluorormethoxy)phenyl]-1,3-thiazol-2-amine (116 mg,0.360 mmol) in the presence of sodium hydride (24 mg, 0.600 mmol) in drytoluene (10 ml) to give 27 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.87 (s, 2H), 7.33(t, J=73.2 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.63 (s, 1H), 7.77 (s, 1H),7.93-7.99 (m, 1H), 8.26 (s, 1H), 12.50 (br s, 1H); APCI-MS (m/z) 541.20(M+H)⁺.

Example 26

N1-{4-[4-(2,2-Dimethylpropoxy)-3-fluorophenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[4-(2,2-dimethylpropoxy)-3-fluorophenyl]-1,3-thiazol-2-amine (101 mg,0.360 mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 27 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 1.02 (s, 9H), 3.18 (s, 3H), 3.43 (s, 3H), 3.74(s, 2H), 3.87 (s, 2H), 7.22 (t, J=8.1 Hz, 1H), 7.56 (s, 1H), 7.62 (s,1H), 7.65-7.70 (m, 1H), 7.73 (s, 1H), 12.43 (br s, 1H); APCI-MS (m/z)501.15 (M+H)⁺.

Example 27N1-{4-[3-Chloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3-chloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-amine (107 mg,0.360 mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 54 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 1.04 (s, 9H), 3.18 (s, 3H), 3.43 (s, 3H), 3.75(s, 2H), 3.87 (s, 2H), 7.18 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 7.62 (s,1H), 7.77-7.85 (m, 1H), 7.95 (s, 1H), 12.42 (br s, 1H); APCI-MS (m/z)517.10 (M+H)⁺.

Example 28N1-{4-[3-Bromo-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3-bromo-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-amine (122 mg,0.360 mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 26 mg of the product as an off-white solid; ¹F1NMR (300 MHz, DMSO-d₆) δ 1.05 (s, 9H), 3.17 (s, 3H), 3.43 (s, 3H), 3.75(s, 2H), 3.87 (s, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.58 (s, 1H), 7.62 (s,1H), 7.86 (d, J=7.8 Hz, 1H), 8.12 (s, 1H), 12.43 (br s, 1H); APCI-MS(m/z) 561.06 (M)⁺.

Example 29N1-[4-(3-Bromo-4-isobutoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-(3-bromo-4-isobutoxyphenyl)-1,3-thiazol-2-amine (118 mg, 0.360 mmol)in the presence of sodium hydride (30 mg, 0.750 mmol) in dry toluene (10ml) to give 40 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 1.02 (d, J=6.6 Hz, 6H), 2.02-2.08 (m, 1H), 3.18 (s, 3H), 3.43(s, 3H), 3.87 (s, 4H), 7.15 (d, J=9.0 Hz, 1H), 7.58 (s, 1H), 7.62 (s,1H), 7.85 (d, J=8.7 Hz, 1H), 8.12 (s, 1H), 12.42 (br s, 1H); APCI-MS(m/z) 547.09 (M)⁺.

Example 30 N1-{4-[3-Fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-amine (105mg, 0.360 mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) indry toluene (10 ml) to give 23 mg of the product as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.16 (s, 3H), 3.41 (s, 3H), 3.86 (s, 2H), 4.87(q, J=8.7 Hz, 2H), 7.34 (t, J=8.7 Hz, 1H), 7.61 (s, 2H), 7.68-7.73 (m,2H), 12.41 (br s, 1H); APCI-MS (m/z) 513.07 (M+H)⁺.

Example 31N1-{4-[3-Chloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3-chloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-amine (111mg, 0.360 mmol) in the presence of sodium hydride (36 mg, 0.900 mmol) indry toluene (10 ml) to give 34 mg of the product as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.18 (s, 3H), 3.43 (s, 3H), 3.87 (s, 2H), 4.91(d, J=8.7 Hz, 2H), 7.35 (d, J=8.7 Hz, 1H), 7.62 (s, 1H), 7.66 (s, 1H),7.86 (d, J=9.0 Hz, 1H), 8.01 (s, 1H), 12.43 (br s, 1H); APCI-MS (m/z)529.15 (M+H)⁺.

Example 32 N1-{4-[3-Bromo-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3-bromo-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-amine (127 mg,0.360 mmol) in the presence of sodium hydride (36 mg, 0.900 mmol) in drytoluene (10 ml) to give 53 mg of the product as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 3.18 (s, 3H), 3.43 (s, 3H), 3.87 (s, 2H), 4.90 (q,J=8.7 Hz, 2H), 7.31 (d, J=8.7 Hz, 1H), 7.62 (s, 1H), 7.66 (s, 1H), 7.91(d, J=9.3 Hz, 1H), 8.16 (s, 1H), 12.43 (br s, 1H); APCI-MS (m/z) 571.27(M−H)⁻.

Example 33N1-[4-(2,4,5,-Trifluorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-(2,4,5-trifluorophenyl)-1,3-thiazol-2-amine (83 mg, 0.360 mmol) in thepresence of sodium hydride (30 mg, 0.750 mmol) in dry toluene (10 ml) togive 20 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.89 (s, 2H), 7.59 (s, 1H), 7.63(s, 1H), 7.70-7.76 (m, 1H), 7.88-8.00 (m, 1H), 12.53 (br s, 1H); APCI-MS(m/z) 451.18 (M+H)⁺.

Example 34N1-[4-(2,3,4-Trichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-(2,3,4-trichlorophenyl)-1,3-thiazol-2-amine (100 mg, 0.429 mmol) inthe presence of sodium hydride (30 mg, 0.750 mmol) in dry toluene (10ml) to give 30 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 3.18 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.63 (s, 1H), 7.68(s, 1H), 7.80 (d, J=8.7 Hz, 2H), 12.51 (br s, 1H); APCI-MS (m/z) 499.39(M−H)⁻.

Example 35N1-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (100 mg, 0.375 mmol) with4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (126 mg,0.450 mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 30 mg of the product as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 3.18 (s, 3H), 3.43 (s, 3H), 3.89 (s, 2H), 7.47-7.56(m, 1H), 7.63 (s, 2H), 8.33 (q, J=6.6 Hz, 1H), 12.54 (br s, 1H); APCI-MS(m/z) 499.39 (M−H)⁻.

Example 36N1-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3,5-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (100 mg,0.360 mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 20 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.89 (s, 2H), 7.63(s, 1H), 7.84 (s, 1H), 7.88 (s, 1H), 8.09 (s, 1H), 12.59 (br s, 1H);APCI-MS (m/z) 500.97 (M+H)⁺.

Example 37N1-{4-[3,5-Difluoro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3,5-difluoro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-amine (100 mg,0.360 mmol) in the presence of sodium hydride (30 mg, 0.751 mmol) in drytoluene (10 ml) to give 25 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.27(t, J=71.7 Hz, 1H), 7.62 (s, 1H), 7.79 (d, J=9.3 Hz, 2H), 7.88 (s, 1H),12.51 (br s, 1H); APCI-MS (m/z) 499.00 (M+H)⁺.

Example 38N1-{4-[3,5-Dichloro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3,5-dichloro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-amine (112 mg,0.360 mmol) in the presence of sodium hydride (36 mg, 0.900 mmol) in drytoluene (10 ml) to give 15 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 3.18 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 7.19(t, J=72.3 Hz, 1H), 7.63 (s, 1H), 7.94 (s, 1H), 8.12 (s, 2H), 12.51 (brs, 1H); APCI-MS (m/z) 529.21 (M−H)⁻.

Example 39N1-{4-[4-(Cyclopropylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[4-(cyclopropylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-amine (102mg, 0.360 mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) indry toluene (10 ml) to give 50 mg of the product as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 0.23-0.30 (m, 2H), 0.50-0.56 (m, 2H), 1.88-1.94(m, 1H), 3.17 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 3.97 (d, J=7.2 Hz,2H), 7.60-7.68 (m, 3H), 7.74 (s, 1H), 12.46 (br s, 1H); APCI-MS (m/z)503.11 (M+H)⁺.

Example 40N1-{4-(3,5-Difluoro-4-isobutoxyphenyl)-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-(3,5-difluoro-4-isobutoxyphenyl)-1,3-thiazol-2-amine (102 mg, 0.360mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 26 mg of the product as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 0.98 (d, J=6.9 Hz, 6H), 1.93-2.04 (m, 1H), 3.18 (s,3H), 3.43 (s, 3H), 3.86-3.93 (m, 4H), 7.60-7.68 (m, 3H), 7.73 (s, 1H),12.45 (br s, 1H); APCI-MS (m/z) 503.29 (M−H)⁻.

Example 41N1-[4-(3,5-Dichloro-4-isobutoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-(3,5-dichloro-4-isobutoxyphenyl)-1,3-thiazol-2-amine (114 mg, 0.360mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 20 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 1.04 (d, J=6.9 Hz, 6H), 2.00-2.14 (m, 1H), 3.17(s, 3H), 3.43 (s, 3H), 3.79 (d, J=5.7 Hz, 2H), 3.87 (s, 2H), 7.63 (s,1H), 7.82 (s, 1H), 8.00 (s, 2H), 12.48 (br s, 1H); APCI-MS (m/z) 537.09(M+H)⁺.

Example 42N1-{4-[3,5-Difluoro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (75 mg, 0.282 mmol) with4-[4-(2,2-dimethylpropoxy)-3,5-difluorophenyl]-1,3-thiazol-2-amine (101mg, 0.338 mmol) in the presence of sodium hydride (28 mg, 0.704 mmol) indry toluene (10 ml) to give 38 mg of the product as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 1.01 (s, 9H), 3.18 (s, 3H), 3.43 (s, 3H), 3.80(s, 2H), 3.88 (s, 2H), 7.60-7.66 (m, 3H), 7.73 (s, 1H), 12.45 (br s,1H); APCI-MS (m/z) 519.14 (M+H)⁺.

Example 43N1-{4-[3,5-Dichloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3,5-dichloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-amine (119mg, 0.360 mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) indry toluene (10 ml) to give 16 mg of the product as an off-white solid;¹H NMR (300 MHz, DMSO-d₆) δ 1.23 (s, 9H), 3.17 (s, 3H), 3.43 (s, 3H),3.67 (s, 2H), 3.88 (s, 2H), 7.63 (s, 1H), 7.83 (s, 1H), 8.00 (s, 2H),12.49 (br s, 1H); APCI-MS (m/z) 551.09 (M+H)⁺.

Example 44N1-{4-[3-Chloro-5-fluoro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3-chloro-5-fluoro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-amine(113 mg, 0.360 mmol) in the presence of sodium hydride (36 mg, 0.900mmol) in dry toluene (10 ml) to give 50 mg of the product as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 1.04 (s, 9H), 3.17 (s, 3H),3.43 (s, 3H), 3.78 (s, 2H), 3.88 (s, 2H), 7.62 (s, 1H), 7.75-7.81 (m,2H), 7.85 (s, 1H), 12.46 (br s, 1H); APCI-MS (m/z) 535.26 (M+H)⁺.

Example 45N1-{4-[3,5-Difluoro-4-(3-methylbutoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3,5-difluoro-4-(3-methylbutoxy)phenyl]-1,3-thiazol-2-amine (107 mg,0.358 mmol) in the presence of sodium hydride (30 mg, 0.750 mmol) in drytoluene (10 ml) to give 40 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 0.92 (d, J=6.3 Hz, 6H), 1.59 (q, J=6.3 Hz, 2H),1.88-1.93 (m, 1H), 3.17 (s, 3H), 3.43 (s, 3H), 3.88 (s, 2H), 4.15 (d,J=6.6 Hz, 2H), 7.60-7.69 (m, 3H), 7.75 (s, 1H), 12.49 (br s, 1H); ESI-MS(m/z) 519.11 (M+H)⁺.

Example 46 N1-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (75 mg, 0.282 mmol) with4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-amine(105 mg, 0.338 mmol) in the presence of sodium hydride (28 mg, 0.704mmol) in dry toluene (10 ml) to give 28 mg of the product as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.88 (s,2H), 4.85 (q, J=8.7 Hz, 2H), 7.62 (s, 1H), 7.70 (d, J=9.3 Hz, 2H), 7.80(s, 1H), 12.48 (br s, 1H); APCI-MS (m/z) 531.08 (M+H)⁺.

Example 47 N1-{4-[3,5-Dichloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3,5-dichloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-amine(123 mg, 0.360 mmol) in the presence of sodium hydride (36 mg, 0.900mmol) in dry toluene (10 ml) to give 17 mg of the product as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H), 3.88 (s,2H), 4.75 (q, J=8.7 Hz, 2H), 7.62 (s, 1H), 7.87 (s, 1H), 8.04 (s, 2H),12.48 (br s, 1H); APCI-MS (m/z) 563.06 (M+H)⁺.

Example 48 N1-{4-[3-Chloro-5-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (80 mg, 0.300 mmol) with4-[3-chloro-5-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-amine(117 mg, 0.360 mmol) in the presence of sodium hydride (30 mg, 0.750mmol) in dry toluene (10 ml) to give 22 mg of the product as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 3.17 (s, 3H), 3.43 (s, 3H),3.88 (s, 2H), 4.83 (q, J=8.7 Hz, 2H), 7.62 (s, 1H), 7.80-7.92 (m, 3H),12.48 (br s, 1H); APCI-MS (m/z) 545.16 (M−H)⁻.

Example 49N1-{4-[3,5-Difluoro-4-(3,3,3-trifluoropropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 1 (57 mg, 0.216 mmol) with4-[3,5-difluoro-4-(3,3,3-trifluoropropoxy)phenyl]-1,3-thiazol-2-amine(70 mg, 0.216 mmol) in the presence of sodium hydride (22 mg, 0.540mmol) in dry toluene (10 ml) to give 17 mg of the product as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 2.74-2.83 (m, 2H), 3.17 (s, 3H), 3.43(s, 3H), 3.88 (s, 2H), 4.30-4.38 (m, 2H), 7.60-7.69 (m, 3H), 7.76 (s,1H), 12.47 (br s, 1H); APCI-MS (m/z) 543.18 (M−H)⁻.

Example 50N1-{4-[4-(Trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.177 mmol) with4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (51 mg, 0.212 mmol) inthe presence of sodium hydride (11 mg, 0.442 mmol) in dry toluene (10ml) to give 32 mg of the product as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 2.32 (s, 3H), 3.16 (s, 3H), 3.41 (s, 3H), 3.84 (s, 2H),7.78-7.86 (m, 3H), 8.12 (d, J=8.4 Hz, 2H), 12.50 (br s, 1H); APCI-MS(m/z) 479.14 (M+H)⁺.

Example 51N1-{4-[3-(Trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.177 mmol) with4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (51 mg, 0.212 mmol) inthe presence of sodium hydride (17 mg, 0.445 mmol) in dry toluene (10ml) to give 30 mg of the product as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 2.32 (s, 3H), 3.16 (s, 3H), 3.42 (s, 3H), 3.83 (s, 2H),7.66-7.74 (m, 2H), 7.87 (s, 1H), 8.19-8.26 (m, 2H), 12.49 (br s, 1H);APCI-MS (m/z) 479.16 (M+H)⁺.

Example 52N1-{4-[3-(Trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.177 mmol) with4-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (55 mg, 0.212 mmol)in the presence of sodium hydride (17 mg, 0.445 mmol) in dry toluene (10ml) to give 12.5 mg of the product as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 2.32 (s, 3H), 3.16 (s, 3H), 3.41 (s, 3H), 3.83 (s, 2H),7.30-7.36 (m, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.81 (s, 1H), 7.87 (s, 1H),7.95 (d, J=7.8 Hz, 1H), 12.48 (br s, 1H); APCI-MS (m/z) 495.11 (M+H)⁺.

Example 53N1-{4-[4-(Trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-[4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (55 mg, 0.214 mmol)in the presence of sodium hydride (10 mg, 0.445 mmol) in dry toluene (10ml) to give 30 mg of the product as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 2.31 (s, 3H), 3.16 (s, 3H), 3.41 (s, 3H), 3.83 (s, 2H), 7.44(d, J=7.8 Hz, 2H), 7.69 (s, 1H), 8.02 (d, J=8.7 Hz, 2H), 12.46 (br s,1H); APCI-MS (m/z) 495.11 (M+H)⁺.

Example 54N1-[4-(3,4-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (40 mg, 0.142 mmol) with4-(3,4-dichlorophenyl)-1,3-thiazol-2-amine (42 mg, 0.171 mmol) in thepresence of sodium hydride (14 mg, 0.355 mmol) in dry toluene (10 ml) togive 25 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83 (s, 2H), 7.21(d, J=8.1 Hz, 1H), 7.83 (s, 1H), 7.89 (d, J=8.7 Hz, 1H), 8.15 (s, 1H),12.47 (br s, 1H); APCI-MS (m/z) 479.09 (M+H)⁺.

Example 55N1-[4-(2,3-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-(2,3-dichlorophenyl)-1,3-thiazol-2-amine (52 mg, 0.214 mmol) in thepresence of sodium hydride (17 mg, 0.445 mmol) in dry toluene (10 ml) togive 45 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.32 (s, 3H), 3.16 (s, 3H), 3.42 (s, 3H), 3.83 (s, 2H), 7.46 (t, J=7.8Hz, 1H), 7.61 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H),12.47 (br s, 1H); APCI-MS (m/z) 479.10 (M+H)⁺.

Example 56N1-[4-(2,4-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-(2,4-dichlorophenyl)-1,3-thiazol-2-amine (52 mg, 0.214 mmol) in thepresence of sodium hydride (17 mg, 0.445 mmol) in dry toluene (10 ml) togive 20 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.31 (s, 3H), 3.16 (s, 3H), 3.41 (s, 3H), 3.83 (s, 2H), 7.54 (dd, J=2.1,8.7 Hz, 1H), 7.64 (s, 1H), 7.73 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 12.46(br s, 1H); APCI-MS (m/z) 479.14 (M+H)¹.

Example 57N1-[4-(2,4-Difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-(2,4-difluorophenyl)-1,3-thiazol-2-amine (46 mg, 0.214 mmol) in thepresence of sodium hydride (18 mg, 0.445 mmol) in dry toluene (10 ml) togive 46 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.32 (s, 3H), 3.16 (s, 3H), 3.41 (s, 3H), 3.83 (s, 2H), 7.22 (t, J=8.4Hz, 1H), 7.38 (t, J=8.7 Hz, 1H), 7.47 (s, 1H), 8.06 (q, J=6.9 Hz, 1H),12.45 (br s, 1H); APCI-MS (m/z) 445.26 (M−H)⁻.

Example 58N1-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (80 mg, 0.285 mmol) with4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (89 mg, 0.339mmol) in the presence of sodium hydride (28 mg, 0.708 mmol) in drytoluene (10 ml) to give 70 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.32 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83(s, 2H), 7.61 (t, J=9.6 Hz, 1H), 7.84 (s, 1H), 8.25-8.31 (m, 2H), 12.50(br s, 1H); APCI-MS (m/z) 497.02 (M−H)⁻.

Example 59N1-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (80 mg, 0.285 mmol) with4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (89 mg, 0.342mmol) in the presence of sodium hydride (28 mg, 0.713 mmol) in drytoluene (10 ml) to give 61 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.32 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.84(s, 2H), 7.87-8.00 (m, 4H), 12.54 (br s, 1H); APCI-MS (m/z) 533.13(M+H)⁺.

Example 60N1-{-4-(2-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (56 mg, 0.213mmol) in the presence of sodium hydride (18 mg, 0.445 mmol) in drytoluene (10 ml) to give 20 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.32 (s, 3H), 3.16 (s, 3H), 3.42 (s, 3H), 3.84(s, 2H), 7.70-7.76 (m, 2H), 7.78-7.86 (m, 1H), 8.26 (t, J=7.8 Hz, 1H),12.55 (br s, 1H); APCI-MS (m/z) 497.07 (M+H)⁺.

Example 61N1-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (100 mg, 0.357 mmol) with4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (112 mg,0.465 mmol) in the presence of sodium hydride (35 mg, 0.875 mmol) in drytoluene (10 ml) to give 85 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.84(s, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.68 (s, 1H), 7.72-7.80 (m, 1H), 8.33(t, J=7.5 Hz, 1H), 12.53 (br s, 1H); APCI-MS (m/z) 497.13 (M+H)¹.

Example 62N1-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (100 mg, 0.356 mmol) with4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (112 mg,0.429 mmol) in the presence of sodium hydride (35 mg, 0.891 mmol) in drytoluene (10 ml) to give 70 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.32 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.84(s, 2H), 7.65 (d, J=8.1 Hz, 1H), 7.99 (s, 1H), 8.07 (d, J=9.9 Hz, 1H),8.13 (s, 1H), 12.52 (br s, 1H); APCI-MS (m/z) 495.49 (M−H)⁻.

Example 63N1-{4-[2-Fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-[2-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (56 mg, 0.213mmol) in the presence of sodium hydride (10 mg, 0.416 mmol) in drytoluene (10 ml) to give 17 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.32 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.84(s, 2H), 7.55-7.65 (m, 1H), 7.69 (s, 1H), 7.76-7.82 (m, 1H), 8.39-8.45(m, 1H), 12.55 (br s, 1H); APCI-MS (m/z) 497.06 (M+H)¹.

Example 64N1-{4-[4-Chloro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (80 mg, 0.285 mmol) with4-[4-chloro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (95 mg, 0.342mmol) in the presence of sodium hydride (29 mg, 0.713 mmol) in drytoluene (10 ml) to give 76 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83(s, 2H), 7.81 (d, J=8.4 Hz, 1H), 7.92 (s, 1H), 8.20 (d, J=8.1 Hz, 1H),8.35 (s, 1H), 12.52 (br s, 1H); APCI-MS (m/z) 513.10 (M+H)⁺.

Example 65N1-{4-[3-Chloro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-[3-chloro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (60 mg, 0.214mmol) in the presence of sodium hydride (18 mg, 0.445 mmol) in drytoluene (10 ml) to give 30 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.32 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83(s, 2H), 7.83 (s, 1H), 8.03 (s, 1H), 8.23 (s, 1H), 8.30 (s, 1H), 12.52(br s, 1H); APCI-MS (m/z) 513.07 (M+H)¹.

Example 66N1-{4-[3-Chloro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-[3-chloro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (59 mg, 0.214mmol) in the presence of sodium hydride (17 mg, 0.445 mmol) in drytoluene (10 ml) to give 50 mg of the product as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 2.32 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.84 (s,2H), 7.93 (d, J=8.1 Hz, 1H), 8.01 (s, 1H), 8.06 (d, J=7.8 Hz, 1H), 8.23(s, 1H), 12.53 (br s, 1H); APCI-MS (m/z) 513.13 (M)⁺.

Example 67N1-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (100 mg, 0.356 mmol) with4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (119 mg,0.428 mmol) in the presence of sodium hydride (35 mg, 0.890 mmol) in drytoluene (10 ml) to give 123 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83(s, 2H), 7.60-7.69 (m, 1H), 7.80-7.90 (m, 2H), 7.95-8.02 (m, 1H), 12.49(br s, 1H); APCI-MS (m/z) 513.26 (M+H)¹.

Example 68N1-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (80 mg, 0.285 mmol) with4-[4-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (95 mg,0.342 mmol) in the presence of sodium hydride (28 mg, 0.708 mmol) in drytoluene (10 ml) to give 70 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83(s, 2H), 7.60 (t, J=9.3 Hz, 1H), 7.79 (s, 1H), 8.00-8.06 (m, 2H), 12.48(br s, 1H); APCI-MS (m/z) 513.15 (M+H)¹.

Example 69N1-{4-[4-Chloro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (80 mg, 0.285 mmol) with4-[4-chloro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (96 mg,0.343 mmol) in the presence of sodium hydride (29 mg, 0.713 mmol) in drytoluene (10 ml) to give 62 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83(s, 2H), 7.77 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.97 (d, J=8.4 Hz, 1H),8.03 (s, 1H), 12.50 (br s, 1H); APCI-MS (m/z) 529.05 (M+H)⁺.

Example 70N1-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (40 mg, 0.142 mmol) with4-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (50 mg,0.169 mmol) in the presence of sodium hydride (14 mg, 0.333 mmol) in drytoluene (10 ml) to give 17 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H), 3.13 (s, 3H), 3.39 (s, 3H), 3.81(s, 2H), 7.63 (d, J=8.4 Hz, 1H), 7.83 (s, 1H), 7.97 (d, J=8.4 Hz, 1H),8.17 (s, 1H), 12.47 (br s, 1H); APCI-MS (m/z) 529.12 (M+H)⁺.

Example 71N1-{4-[3-Chloro-5-(trifluoromethoxyphenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (40 mg, 0.142 mmol) with4-[3-chloro-5-(trifluoromethoxy)phenyl]-1,3-thiazol-2-amine (50 mg,0.169 mmol) in the presence of sodium hydride (14 mg, 0.333 mmol) in drytoluene (10 ml) to give 29 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83(s, 2H), 7.54 (s, 1H), 7.88 (s, 1H), 7.97 (s, 1H), 8.05 (s, 1H), 12.50(br s, 1H); APCI-MS (m/z) 529.11 (M+H)⁺.

Example 72N1-{4-[3-Chloro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-[3-chloro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-amine (59 mg, 0.214mmol) in the presence of sodium hydride (17 mg, 0.445 mmol) in drytoluene (10 ml) to give 25 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83(s, 2H), 7.09 (t, J=72.6 Hz), 7.45 (d, J=8.1 Hz, 1H), 7.76 (s, 1H),7.91-7.95 (d, J=8.7 Hz, 1H), 8.11 (s, 1H), 12.46 (br s, 1H); ESI-MS(m/z) 511.08 (M+H)⁺.

Example 73 N1-{4-[3-Fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-[3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-amine (62 mg,0.214 mmol) in the presence of sodium hydride (17 mg, 0.445 mmol) in drytoluene (10 ml) to give 75 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.82(s, 2H), 4.89 (q, J=9.0 Hz, 2H), 7.37 (t, J=9.0 Hz, 1H), 7.63 (s, 1H),7.70-7.76 (m, 1H), 7.80 (s, 1H), 12.42 (br s, 1H); APCI-MS (m/z) 527.15(M+H)⁺.

Example 74 N1-{4-[3-Chloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-[3-chloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-amine (66 mg,0.214 mmol) in the presence of sodium hydride (17 mg, 0.445 mmol) in drytoluene (10 ml) to give 21 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.82(s, 2H), 4.92 (q, J=9.0 Hz, 2H), 7.35 (d, J=8.7 Hz, 1H), 7.66 (s, 1H),7.84-7.90 (m, 1H), 8.01 (s, 1H), 12.42 (br s, 1H); APCI-MS (m/z) 543.92(M+H)⁺.

Example 75N1-[4-(2,4,5-Trifluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-(2,4,5-Trifluorophenyl)-1,3-thiazol-2-amine (49 mg, 0.212 mmol) in thepresence of sodium hydride (10 mg, 0.416 mmol) in dry toluene (10 ml) togive 21 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 2.32 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.84 (s, 2H), 7.57(s, 1H), 7.67-7.77 (s, 1H), 7.90-7.99 (m, 1H), 12.49 (br s, 1H); APCI-MS(m/z) 465.06 (M+H)⁺.

Example 76N1-[4-(3,4,5-Trifluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (40 mg, 0.142 mmol) with4-(3,4,5-trifluorophenyl)-1,3-thiazol-2-amine (39 mg, 0.171 mmol) in thepresence of sodium hydride (14 mg, 0.355 mmol) in dry toluene (10 ml) togive 25 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83 (s, 2H),7.76-7.85 (m, 3H), 12.48 (br s, 1H); APCI-MS (m/z) 465.09 (M+H)⁺.

Example 77N1-[4-(2,3,4-Trifluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-(2,3,4-trifluorophenyl)-1,3-thiazol-2-amine (49 mg, 0.214 mmol) in thepresence of sodium hydride (18 mg, 0.445 mmol) in dry toluene (10 ml) togive 45 mg of the product as an off-white solid; ¹F1 NMR (300 MHz,DMSO-d₆) δ 2.32 (s, 3H), 3.16 (s, 3H), 3.41 (s, 3H), 3.84 (s, 2H),7.43-7.46 (m, 1H), 7.57 (s, 1H), 7.82-7.85 (m, 1H), 12.50 (br s, 1H);ESI-MS (m/z) 465.06 (M+H)⁺.

Example 78N1-[4-(3-Chloro-2,4-difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (40 mg, 0.142 mmol) with4-(3-chloro-2,4-difluorophenyl)-1,3-thiazol-2-amine (42 mg, 0.170 mmol)in the presence of sodium hydride (14 mg, 0.333 mmol) in dry toluene (10ml) to give 20 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83 (s, 2H), 7.45(t, J=8.1 Hz, 1H), 7.58 (s, 1H), 8.02 (q, J=6.9 Hz, 1H), 12.50 (br s,1H); APCI-MS (m/z) 481.09 (M+H)⁺.

Example 79N1-[4-(2,4-Dichloro-5-fluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-(2,4-dichloro-5-fluorophenyl)-1,3-thiazol-2-amine (56 mg, 0.214 mmol)in the presence of sodium hydride (21 mg, 0.534 mmol) in dry toluene (10ml) to give 24 mg of the product as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 2.27 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83 (s, 2H), 7.77(s, 1H), 7.85-7.96 (m, 2H), 12.50 (br s, 1H); APCI-MS (m/z) 497.06(M+H)⁺.

Example 80N1-{4-(2,2-Dimethylpropoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}-2(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (80 mg, 0.285 mmol) with4-[4-(2,2-dimethylpropoxy)-3,5-difluorophenyl]-1,3-thiazol-2-amine (102mg, 0.342 mmol) in the presence of sodium hydride (28 mg, 0.713 mmol) indry toluene (10 ml) to give 41 mg of the product as an off-white solid;¹H NMR (300 MHz, DMSO-d₆) δ 1.01 (s, 9H), 2.31 (s, 3H), 3.15 (s, 3H),3.41 (s, 3H), 3.80 (s, 2H), 3.82 (s, 2H), 7.64 (d, J=9.3 Hz, 2H), 7.74(s, 1H), 12.44 (br s, 1H); APCI-MS (m/z) 497.07 (M+H)⁺.

Example 81N1-[4-(3,5-Difluoro-4-isobutoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-(3,5-difluoro-4-isobutoxyphenyl)-1,3-thiazol-2-amine (60 mg, 0.214mmol) in the presence of sodium hydride (28 mg, 0.445 mmol) in drytoluene (10 ml) to give 38 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 0.98 (d, J=6.6 Hz, 6H), 1.92-2.03 (m, 1H), 2.31(s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.82 (s, 2H), 3.91 (d, J=6.3 Hz,2H), 7.63 (d, J=9.3 Hz, 2H), 7.73 (s, 1H), 12.44 (br s, 1H); APCI-MS(m/z) 519.19 (M+H)⁺.

Example 82N1-[4-(3,5-Dichloro-4-isobutoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-(3,5-dichloro-4-isobutoxyphenyl)-1,3-thiazol-2-amine (68 mg, 0.214mmol) in the presence of sodium hydride (18 mg, 0.445 mmol) in drytoluene (10 ml) to give 35 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 1.05 (d, J=6.9 Hz, 6H), 2.27 (s, 3H), 3.15 (s,3H), 3.41 (s, 3H), 3.78-3.83 (m, 4H), 7.82 (s, 1H), 8.01 (s, 2H), 12.45(br s, 1H); ESI-MS (m/z) 551.10 (M+H)⁺.

Example 83

N1-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (80 mg, 0.285 mmol) with4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (96 mg,0.343 mmol) in the presence of sodium hydride (29 mg, 0.713 mmol) in drytoluene (10 ml) to give 85 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.32 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.84(s, 2H), 7.53 (t, J=9.3 Hz, 1H), 7.64 (s, 1H), 8.33-8.35 (m, 1H), 12.53(br s, 1H); APCI-MS (m/z) 515.24 (M+H)⁺.

Example 84N1-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (80 mg, 0.285 mmol) with4-[3,5-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine (95 mg,0.342 mmol) in the presence of sodium hydride (28.5 mg, 0.712 mmol) indry toluene (15 ml) to give 86 mg of the product as an off-white solid;¹H NMR (300 MHz, DMSO-d₆) δ 2.32 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H),3.84 (s, 2H), 7.84 (s, 1H), 7.88 (s, 1H), 8.08 (s, 1H), 12.56 (br s,1H); APCI-MS (m/z) 515.04 (M+H)⁺.

Example 85N1-{4-[3,5-Difluoro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-[3,5-difluoro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-amine (59 mg,0.212 mmol) in the presence of sodium hydride (17 mg, 0.445 mmol) in drytoluene (10 ml) to give 30 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83(s, 2H), 7.28 (t, J=72.3 Hz, 1H), 7.79 (d, J=9.9 Hz, 2H), 7.88 (s, 1H),12.50 (br s, 1H); APCI-MS (m/z) 513.11 (M+H)⁺.

Using the similar procedure as described in method A or B, additionalexamples of furopyrimindiedione acetamides with multiple fluorinesubstitutions (as depicted in Table 3) can be prepared by coupling2,4-dioxofuropyrimidinyl acetic acid or their ester with an appropriatefluorinated 2-amino-4-arylthiazole selected from Table 2.

TABLE 3 Additional examples of fluorinated furopyrimindiedione acetamidederivatives S Mol. Mol No. Molecular structure Chemical name Formula Wt. 1

N1-{4-[2,6-Difluoro-4- (trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6- trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5- yl)acetamide C₂₁H₁₅F₅N₄O₄S514.43  2

N1-{4-[2,5-Difluoro-4- (trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6- trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5- yl)acetamide C₂₁H₁₅F₅N₄O₅S530.43  3

N1-{4-[2,5-Difluoro-4- (difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6- trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5- yl)acetamide C₂₁H₁₆F₄N₄O₅S512.44  4

N1-{4-[2,5-Difluoro-4- (trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6- trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5- yl)acetamide C₂₁H₁₅F₅N₄O₄S514.43  5

N1-{4-[2,3-Difluoro-5- (trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6- trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5- yl)acetamide C₂₁H₁₅F₅N₄O₄S514.43  6

N1-{4-[2,5-Difluoro-3- (trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6- trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5- yl)acetamide C₂₁H₁₅F₅N₄O₄S514.43  7

N1-{4-[2,4-Difluoro-5- (trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6- trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5- yl)acetamide C₂₁H₁₅F₅N₄O₄S514.43  8

N1-{4-[2,6-Difluoro-5- (trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6- trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5- yl)acetamide C₂₁H₁₅F₅N₄O₄S514.43  9

N1-{4-[2,3-Difluoro-4- (trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6- trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5- yl)acetamide C₂₁H₁₅F₅N₄O₄S514.43 10

N1-{4-[2,4-Difluoro-3- (trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6- trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5- yl)acetamide C₂₁H₁₅F₅N₄O₅S530.43 11

N1-{4-[2,3-Difluoro-4- (trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6- trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5- yl)acetamide C₂₁H₁₅F₅N₄O₅S530.43 12

N1-{4-[2-Fluoro-4- (trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6- trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5- yl)acetamide C₂₁H₁₆F₄N₄O₅S512.44 13

N1-{4-[2,4-Difluoro-3- (difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6- trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5- yl)acetamide C₂₁H₁₆F₄N₄O₅S512.44 14

N1-{4-[2,3-Difluoro-4- (difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6- trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5- yl)acetamide C₂₁H₁₆F₄N₄O₅S512.44 15

N1-{4-2-Fluoro-4- (difluoromethoxy)phenyl]- 1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo- 1,2,3,4-tetrahydrofuro[2,3- d]pyrimidin-5-yl)acetamide C₂₁H₁₇F₃N₄O₅S 494.44

Example 86N1-{4-[3,5-Dichloro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.170 mmol) with4-[3,5-dichloro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-amine (62 mg,0.200 mmol) in the presence of sodium hydride (16 mg, 0.420 mmol) in drytoluene (10 ml) to give 60 mg of the product as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83(s, 2H), 7.20 (t, J=72.0 Hz, 1H), 7.94 (s, 1H), 8.12 (s, 2H), 12.49 (brs, 1H); APCI-MS (m/z) 545.12 (M+H)⁺.

Example 87N1-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (80 mg, 0.285 mmol) with4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-amine(106 mg, 0.343 mmol) in the presence of sodium hydride (29 mg, 0.713mmol) in dry toluene (10 ml) to give 64 mg of the product as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H),3.41 (s, 3H), 3.83 (s, 2H), 4.87 (q, J=8.7 Hz, 2H), 7.69 (s, 1H), 7.72(s, 1H), 7.80 (s, 1H), 12.47 (br s, 1H); APCI-MS (m/z) 545.07 (M+H)⁺.

Example 88 N1-{4-[3,5-Dichloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (42 mg, 0.150 mmol) with4-[3,5-dichloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-amine (62mg, 0.180 mmol) in the presence of sodium hydride (14 mg, 0.370 mmol) indry toluene (10 ml) to give 17 mg of the product as an off-white solid;¹H NMR (300 MHz, DMSO-d₆) δ 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H),3.83 (s, 2H), 4.76 (q, J=8.7 Hz, 2H), 7.87 (s, 1H), 8.05 (s, 2H), 12.47(br s, 1H); APCI-MS (m/z) 577.45 (M+H)⁺.

Example 89N1-{4-[4-(Cyclopropylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-[4-(cyclopropylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-amine (60mg, 0.214 mmol) in the presence of sodium hydride (17 mg, 0.445 mmol) indry toluene (10 ml) to give 19 mg of the product as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 0.23-0.30 (m, 2H), 0.50-0.56 (m, 2H), 1.18-1.24(m, 1H), 2.31 (s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 3.83 (s, 2H), 3.97(d, J=7.2 Hz, 2H), 7.62 (s, 1H), 7.74 (s, 1H), 12.45 (br s, 1H); APCI-MS(m/z) 517.14 (M+H)¹.

Example 90N1-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method A) by coupling Intermediate 3 (50 mg, 0.178 mmol) with4-[4-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazol-2-amine (59mg, 0.214 mmol) in the presence of sodium hydride (17 mg, 0.445 mmol) indry toluene (10 ml) to give 26 mg of the product as a white solid; ¹HNMR (300 MHz, CDCl₃) δ 2.41 (s, 3H), 2.47 (s, 3H), 3.47 (s, 3H), 3.54(s, 3H), 3.70 (s, 2H), 7.18-7.26 (m, 1H), 7.76-7.83 (m, 1H), 7.85-7.90(m, 1H), 11.42 (br s, 1H); APCI-MS (m/z) 511.08 (M+H)¹.

Example 91N1-[5-(4-Bromophenyl)-1,3,4-thiadiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure(Method B) by coupling Intermediate 4 (45 mg, 0.178 mmol) with5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine (45 mg, 0.178 mmol) in thepresence of EDCI hydrochloride (40 mg, 0.214 mmol), HOBt (7 mg, 0.053mmol) and DMAP (2 mg, 0.017 mmol) in 1,2-dichloroethane (5 ml) to give13 mg of the product as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 2.32(s, 3H), 3.15 (s, 3H), 3.41 (s, 3H), 4.03 (s, 2H), 7.66-7.75 (m, 2H),7.84-7.90 (m, 2H), 12.89 (br s, 1H); APCI-MS (m/z) 490.09 (M)⁺.

Pharmacological Activity

The illustrative examples of the present invention are screened forTRPA1 activity according to a modified procedure described in (a) Tóth,A. et al. Life Sciences, 2003, 73, 487-498. (b) McNamara C, R. et al,Proc. Natl. Acad. Sci. U.S.A., 2007, 104, 13525-13530. The screening ofthe compounds can be carried out by other methods and procedures knownto persons skilled in the art.

Screening for TRPA1 Antagonist Using the ⁴⁵Calcium Uptake Assay:

The inhibition of TRPA1 receptor activation was measured as inhibitionof allyl isothiocyanate (AITC) induced cellular uptake of radioactivecalcium.

Test compounds were dissolved in 100% DMSO to prepare 10 mM stock andthen diluted using plain medium with 0.1% BSA and 1.8 mM CaCl₂ to getthe desired concentration. The final concentration of DMSO in thereaction was 0.5% (v/v). Human TRPA1 expressing CHO cells were grown inF-12 DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, and400 μg/ml of G-418. Rat TRPA1 expressing CHO cells were grown in F-12DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, and 400μg/ml of Zeocin. Cells were seeded 24 h prior to the assay in 96 wellplates so as to get ˜50,000 cells per well on the day of experiment.Cells were treated with the test compounds for 10 minutes followed bythe addition of AITC at a final concentration of 30 μM (for human TRPA1)and/or 10 μM (for rat TRPA1) and 5 μCi/ml ⁴⁵Ca⁺² for 3 minutes. Cellswere washed and lysed using a buffer containing 1% Triton X-100, 0.1%deoxycholate and 0.1% SDS. Radioactivity in the lysate was measured in aPackard TopCount after addition of liquid scintillant. (Toth et al, LifeSciences (2003) 73, 487-498; McNamara C R et al, Proceedings of theNational Academy of Sciences, (2007) 104, 13525-13530).

Concentration response curves were plotted as a % of maximal responseobtained in the absence of test antagonist. IC₅₀ values can becalculated from concentration response curve by nonlinear regressionanalysis using GraphPad PRISM software.

The compounds prepared were tested using the above assay procedure andthe results obtained are given in Table 4. Percentage inhibition atconcentrations of 1.0 μM and 10.0 μM are given in the table along withIC₅₀ (nM) details for selected examples. The IC₅₀ (nM) values of thecompounds are set forth in Table 4 wherein “A” refers to an IC₅₀ valueof less than 50 nM, “B” refers to IC₅₀ value in range of 50.01 to 100.0nM and “C” refers to IC₅₀ value of more than 100.0 nM

TABLE 4 In-vitro screening results of compounds of invention: humanTRPA1 rat TRPA1 Percentage inhibition IC₅₀ Percentage inhibition IC₅₀ at1.0 at 10.0 value at 11.0 at 10.0 value Examples μM μM (nM) μM μM (nM)Example 1 C 96.65 100.00 — Example 2 17.67 28.43 ND ND — Example 3 6.4445.83 — ND ND — Example 4 14.52 57.32 — ND ND — Example 5 27.04 99.75 —ND ND — Example 6 100 99.58 A — Example 7 98.76 99.75 A — Example 893.15 98.82 A 100.00 100.00 A Example 9 99.33 100 A — Example 98.5497.71 A 97.55 100.00 B 10 Example 98.75 99.37 B ND ND — 11 Example 97.9498.38 C ND ND — 12 Example 98.53 99.36 A C 13 Example 99.39 99.74 A100.00 100.00 A 14 Example 99.9 99.85 A 100.00 98.95 A 15 Example 98.5199.17 A 99.96 98.63 A 16 Example 99.94 99.97 A 97.71 99.83 B 17 Example99.9 100 A 99.90 94.08 B 18 Example 99.9 100 A 98.88 98.22 B 19 Example98.48 97.55 A 96.80 99.79 A 20 Example 99.85 99.8 A 98.88 99.90 A 21Example 99.26 98.47 A 100.00 100.00 — 22 Example 96.35 99.02 A 92.5795.54 C 23 Example 97.4 99.85 A 100.00 99.62 C 24 Example 99.33 99.83 A— 25 Example 97.57 99.31 A 98.59 99.87 — 26 Example 97.14 99.2 C 93.13100.00 — 27 Example 96.71 99.31 C 98.46 100.00 — 28 Example 98.63 99.81C — 29 Example 97.43 100 A 97.09 100.00 C 30 Example 98.32 99.82 A 96.75100.00 B 31 Example 99.8 99.54 A 85.16 100.00 A 32 Example 97.87 98.1 A— 33 Example 97.05 99.72 A 91.01 99.27 B 34 Example 99.85 98.38 A A 35Example 99.73 99.6 A 100.00 100.00 B 36 Example 99.9 99.74 A 100.00100.00 B 37 Example 99.79 99.9 A 67.01 100.00 C 38 Example 94.18 98.68 AC 39 Example 93.2 99.17 A 99.20 99.57 A 40 Example 99.56 100 A 99.53100.00 A 41 Example 96.13 99.9 A A 42 Example 99.23 99.7 A 89.21 100.00B 43 Example 100 99.51 A 71.04 99.25 A 44 Example 90.67 98.14 A — 45Example 99.85 100 A 96.12 99.54 B 46 Example 99.18 99.8 A 86.03 100.00 A47 Example 96.59 95.12 A 99.58 99.16 A 48 Example 95.58 98.26 A 86.6297.70 A 49 Example 99.64 98.35 — 99.87 100 — 50 Example 99.77 99.96 —100 100 — 51 Example 99.08 99.15 — 100 100 — 52 Example 99.73 97.28 —100 100 — 53 Example — — A B 54 Example 95.83 99.03 — 97.66 100 — 55Example — — — — 56 Example — — — — 57 Example — — A A 58 Example — — A B59 Example — — A 99.32 99.65 B 60 Example — — A A 61 Example — — A A 62Example — — B 97.63 99.80 — 63 Example — — A A 64 Example — — A 99.7999.80 B 65 Example 99.38 99.85 99.85 98.50 — 66 Example — — A A 67Example — — A A 68 Example — — A A 69 Example — — A A 70 Example — — A B71 Example — — A 100 100 C 72 Example — — A 100 100 — 73 Example — — A100 100 A 74 Example — — 18.54 B 75 Example — — 7.65 B 76 Example — —19.23 99.15 98.55 — 77 Example — — 34.5 94.5 94.8 — 78 Example — — 247.1ND ND — 79 Example — — 3.63 A 80 Example — — 4.63 100 99.25 B 81 Example— — 3.34 99.96 100 A 82 Example — — 4.52 A 83 Example — — 4.16 A 84Example — — 6.57 100 100 — 85 Example — — 4.11 99.12 95.41 A 86 Example— — 1.68 A 87 Example — — 1.77 98.26 100 — 88 Example — — 9.72 98.81 B89 Example — — 14.18 97.98 99.52 — 90

1.-42. (canceled)
 43. A compound of the formula (I)

or a pharmaceutically acceptable salt thereof, wherein, R¹ and R², whichmay be the same or different, are independently selected from hydrogen,substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, arylalkyl, (CR^(x)R^(Y))_(n)OR^(x), C(O)R^(x),C(O)OR^(x), C(O)NR^(x)R^(y), (CH₂)_(n)NR^(x)R^(y),(CH₂)_(n)CHR^(x)R^(y), NR^(x)(CR^(x)R^(Y))_(n)CONR^(x)R^(Y),(CH₂)_(n)NR^(x)R^(y) and (CH₂)_(n)NHC(O)R^(x); R³ is selected fromhydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl and cycloalkenyl; Z₁ and Z₂ areindependently oxygen or CR^(a); with a proviso that one of Z₁ or Z₂ isalways oxygen and other is CR^(a); L is a linker selected from—(CR^(x)R^(y))_(n)—, —O—(CR^(x)R^(y))_(n)—, —C(O)—, —NR^(x)—,—S(O)_(m)NR^(x)—, —NR^(x)(CR^(x)R^(y))_(n)— and—S(O)_(m)NR^(x)(CR^(x)R^(y))_(n); at each occurrence, R^(a) is selectedfrom hydrogen, cyano, substituted or unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, biaryl,heteroaryl, heteroarylalkyl, heterocyclic ring, heterocyclylalkyl,OR^(x), (CR^(x)R^(y))_(n)OR^(x), C(O)R^(x), C(O)OR^(x), C(O)NR^(x)R^(y),S(O)_(m)NR^(x)R^(y), NR^(x)R^(y), NR^(x)(CR^(x)R^(y))_(n)OR^(x),(CH₂)_(n)NR^(x)R^(Y), (CH₂)_(n)CHR^(x)R^(y),NR^(x)(CR^(x)R^(Y))_(n)C(O)NR^(x)R^(Y), (CH₂)_(n)NHC(O)R^(x),(CH₂)_(n)NH(CH₂)_(n)SO₂R^(x), (CH₂)_(n)NHSO₂R^(x), SR^(x) and OR^(x); Uis selected from —(CR^(x)R^(y))_(n)—, substituted or unsubstituted aryl,substituted or unsubstituted five membered heterocycles selected fromthe group consisting of thiazole, isothiazole, oxazole, isoxazole,thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene, pyrrole,1,2,3-triazole and 1,2,4-triazole, or substituted or unsubstituted sixmembered heterocycle selected from the group consisting of pyrimidine,pyridine and pyridazine; V is selected from hydrogen, cyano, nitro,—NR^(x)R^(y), halogen, hydroxyl, substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl,haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl,heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, —C(O)OR^(x),—OR^(x), —C(O)NR^(x)R^(y), —C(O)R^(x) and —SO₂NR^(x)R^(y); oralternatively U and V together may form an optionally substituted 3 to 7membered saturated or unsaturated cyclic ring that may optionallyinclude one or more heteroatoms selected from O, S and N; at eachoccurrence, R^(x) and R^(y) are independently selected from hydrogen,hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclic ring and heterocyclylalkyl and at eachoccurrence, ‘m’ and ‘n’ are independently selected from 0 to 2, bothinclusive.
 44. The compound according to claim 43, wherein Z₁ is oxygenand Z₂ is CR^(a).
 45. The compound according to claim 43, wherein Z₂ isoxygen and Z₁ is CR^(a).
 46. The compound according to claim 43, whereinR^(a) is hydrogen.
 47. The compound according to claim 43, wherein R^(a)is methyl.
 48. The compound according to claim 43, wherein L is CH₂. 49.The compound according to claim 43, wherein R¹ and R² are (C₁-C₄) alkyl.50. The compound according to claim 49, wherein (C₁-C₄) alkyl is methyl.51. The compound according to claim 43, wherein R³ is hydrogen.
 52. Thecompound according to claim 43, wherein U is thiazole, imidazole,isoxazole, pyrazole, thiadiazole or pyrimidine.
 53. The compoundaccording to claim 43, wherein V is substituted or unsubstituted aryl.54. The compound according to claim 53, wherein aryl is phenyl.
 55. Thecompound of claim 43 having the formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R^(a), Uand V are as defined for claim
 43. 56. The compound according to claim55, wherein R¹ and R² are (C₁-C₄) alkyl.
 57. The compound according toclaim 56, wherein (C₁-C₄) alkyl is methyl.
 58. The compound according toclaim 55, wherein R^(a) is hydrogen or (C₁-C₄) alkyl.
 59. The compoundaccording to claim 55, wherein U is thiazole, imidazole, isoxazole,pyrazole, thiadiazole or pyrimidine.
 60. The compound according to claim55, wherein V is substituted or unsubstituted aryl.
 61. The compoundaccording to claim 60, wherein aryl is phenyl.
 62. The compoundaccording to claim 43:

or a pharmaceutically acceptable salt thereof, wherein, R¹, R² andR^(a), which may be the same or different, are each independentlyhydrogen or (C₁-C₄)alkyl; and R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹, which may besame or different, are each independently selected from the groupcomprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino,substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy,cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl,arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring andheterocyclylalkyl.
 63. The compound according to claim 62 wherein R^(a)is hydrogen
 64. The compound according to claim 62 wherein R^(a) is(C₁-C₄) alkyl.
 65. The compound according to claim 62 wherein R¹ and R²are (C₁-C₄) alkyl.
 66. The compound according to claim 65, wherein(C₁-C₄) alkyl is methyl.
 67. The compound according to claim 62, whereinR⁴ and R⁵ are independently selected from the group consisting ofhydrogen, fluoro, trifluoromethyl or trifluoromethoxy.
 68. The compoundaccording to claims 62, wherein R⁶ and R⁷ are independently selectedfrom the group consisting of hydrogen, fluoro, trifluoromethyl ortrifluoromethoxy.
 69. The compound according to claim 62, wherein R⁸ ishydrogen.
 70. The compound according to claim 62, wherein R⁹ ishydrogen.
 71. The compound according to claim 62, wherein R⁹ is methyl.72. The compound selected from:N1-[4-(4-Trifluoromethylphenoxy)phenyl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[2-(2,4-Dichlorophenyl)ethyl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(Trifluoromethyl)-1,3-thiazol-2-yl]-2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N-(4,6-Difluoro-1,3-benzothiazol-2-yl)-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(4-Isobutylphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-(Trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-(Trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N-1-[4-(4-Trifluorormethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(3-Trifluorormethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(3-Bromo-4-fluorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(3,4-Difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(2,4-Difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(3,4-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-Chloro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-Chloro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[2-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(3-Fluoro-4-difluoromethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(3-Chloro-4-difluoromethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;andN1-[4-(3-Bromo-4-difluoromethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-(2,2-Dimethylpropoxy)-3-fluorophenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Chloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Bromo-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(3-Bromo-4-isobutoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Chloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Bromo-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(2,4,5,-Trifluorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(2,3,4-Trichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3,5-Difluoro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3,5-Dichloro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-(Cyclopropylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-(3,5-Difluoro-4-isobutoxyphenyl)-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(3,5-Dichloro-4-isobutoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3,5-Difluoro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3,5-Dichloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Chloro-5-fluoro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3,5-Difluoro-4-(3-methylbutoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3,5-Dichloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Chloro-5-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;andN1-{4-[3,5-Difluoro-4-(3,3,3-trifluoropropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-(Trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-(Trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{₄-[3-(Trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-(Trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(3,4-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(2,3-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(2,4-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(2,4-Difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[2-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[2-Fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-Chloro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Chloro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Chloro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-Chloro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;andN1-{4-[3-Chloro-5-(trifluoromethoxyphenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Chloro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3-Chloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-[2,4,5-Trifluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(3,4,5-Trifluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(2,3,4-Trifluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(3-Chloro-2,4-difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(2,4-Dichloro-5-fluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-(2,2-Dimethylpropoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(3,5-Difluoro-4-isobutoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-[4-(3,5-Dichloro-4-isobutoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3,5-Difluoro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3,5-Dichloro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[3,5-Dichloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-(Cyclopropylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;N1-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;andN1-[5-(4-Bromophenyl)-1,3,4-thiadiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;or a pharmaceutically acceptable salt thereof.
 73. The compound havingformula

or pharmaceutically acceptable salt thereof.
 74. The compound havingformula

or pharmaceutically acceptable salt thereof.
 75. A pharmaceuticalcomposition comprising one or more compound according to claim 43, andone or more pharmaceutically acceptable excipients, carriers, diluentsor mixture thereof.
 76. A method for treating disease or conditionassociated with TRPA1 function in a subject in need thereof comprisingadministering to the subject an effective amount of a compound accordingto claim
 43. 77. The method according to claim 76, wherein the symptomsof a disease or condition associated with TRPA1 function is selectedfrom pain, chronic pain, complex regional pain syndrome, neuropathicpain, postoperative pain, rheumatoid arthritic pain, osteoarthriticpain, back pain, visceral pain, cancer pain, algesia, neuralgia,migraine, neuropathies, diabetic neuropathy, sciatica, HIV-relatedneuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury,ischaemia, neurodegeneration, stroke, post stroke pain, multiplesclerosis, respiratory diseases, asthma, cough, COPD, inflammatorydisorders, oesophagitis, gastroeosophagal reflux disorder (GERD),irritable bowel syndrome, inflammatory bowel disease, pelvichypersensitivity, urinary incontinence, cystitis, burns, psoriasis,eczema, emesis, stomach duodenal ulcer and pruritus.
 78. The methodaccording to claim 77, wherein the symptoms of a disease or condition isassociated with chronic pain.
 79. The method according to claim 77,wherein the symptoms of a disease or condition is associated withneuropathic pain.
 80. The method according to claim 77, wherein thesymptoms of a disease or condition is associated with rheumatoidarthritic pain or osteoarthritic pain.